System and method for inducing hypothermia with control and determination of catheter pressure

ABSTRACT

Embodiments of the invention provide a system for temperature control of the human body. The system includes an indwelling catheter with a tip-mounted heat transfer element. The catheter is fluidically coupled to a console that provides a heated or cooled heat transfer working fluid to exchange heat with the heat transfer element, thereby heating or cooling blood. The heated or cooled blood then heats or cools the patient&#39;s body or a selected portion thereof. In particular, methods and devices are provided for control and determination of the pressure within the heat transfer element.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. provisionalpatent application serial Nos. 60/449,815 for “Alternate Methods OfPressure Measurement,” filed Feb. 24, 2003, and 60/449,764 for “Methodof Setting Pressure Within A Heat Transfer Element,” filed Feb. 24,2003, both of which are incorporated herein.

FIELD OF THE INVENTION

[0002] The present invention relates generally to the lowering, raising,and control of the temperature of the human body. More particularly, theinvention relates to a method and intravascular apparatus forcontrolling the temperature of the human body.

BACKGROUND

[0003] Background Information—Organs in the human body, such as thebrain, kidney and heart, are maintained at a constant temperature ofapproximately 37° C. Hypothermia can be clinically defined as a corebody temperature of 35° C. or less. Hypothermia is sometimescharacterized further according to its severity. A body core temperaturein the range of 33° C. to 35° C. is described as mild hypothermia. Abody temperature of 28° C. to 32° C. is described as moderatehypothermia. A body core temperature in the range of 24° C. to 28° C. isdescribed as severe hypothermia.

[0004] Hypothermia is uniquely effective in reducing ischemia. Forexample, it is effective in reducing brain injury caused by a variety ofneurological insults and may eventually play an important role inemergency brain resuscitation. Experimental evidence has demonstratedthat cerebral cooling improves outcome after global ischemia, focalischemia, or traumatic brain injury. For this reason, hypothermia may beinduced in order to reduce the effect of certain bodily injuries to thebrain as well as ischemic injuries to other organs.

BRIEF DESCRIPTION OF THE DRAWINGS

[0005] The novel features of this invention, as well as the inventionitself, will be best understood from the attached drawings, taken alongwith the following description, in which similar reference charactersrefer to similar parts, and in which:

[0006]FIG. 1 is a schematic representation of the heat transfer elementbeing used in an embodiment within the superior vena cava;

[0007]FIG. 2 is an elevational view of a mixing inducing heat transferelement within a blood vessel;

[0008]FIG. 3 is a schematic diagram of a heat transfer element accordingto an embodiment of the invention;

[0009]FIG. 4 is a graph showing the relationship between the Nusseltnumber (Nu) and the Reynolds number (Re) for air flowing through a longheated pipe at uniform wall temperature;

[0010]FIG. 5 is an elevation view of one embodiment of a heat transferelement according to the invention;

[0011]FIG. 6 is a longitudinal section view of the heat transfer elementof FIG. 5;

[0012]FIG. 7 is a transverse section view of the heat transfer elementof FIG. 5;

[0013]FIG. 8 is a perspective view of the heat transfer element of FIG.5 in use within a blood vessel;

[0014]FIG. 9 is a perspective view of another embodiment of a heattransfer element according to the invention, with aligned longitudinalridges on adjacent segments;

[0015]FIG. 10 is a transverse section view of the heat transfer elementof FIG. 9;

[0016]FIG. 11 is a cut-away perspective view of an alternativeembodiment of a heat transfer element according to the invention;

[0017]FIG. 12 is a transverse section view of the heat transfer elementof FIG. 11;

[0018]FIG. 13 is a front sectional view of a further embodiment of acatheter employing a heat transfer element according to the principlesof the invention further employing a side-by-side lumen arrangementconstructed in accordance with an embodiment of the invention;

[0019]FIG. 14 is a cross-sectional view of the catheter of FIG. 13 takenalong line 14-14 of FIG. 13;

[0020]FIG. 15 is a front sectional view of a catheter employing a heattransfer element and lumen arrangement constructed in accordance with afurther embodiment of the invention;

[0021]FIG. 16 is a front sectional view of a catheter employing a heattransfer element and lumen arrangement constructed in accordance with astill further embodiment of the invention;

[0022]FIG. 17 is a front sectional view of another embodiment of acatheter employing a heat transfer element according to the principlesof the invention further employing a side-by-side lumen arrangementconstructed in accordance with another embodiment of the invention;

[0023]FIG. 18 is a cross-sectional view of the heat transfer elementillustrated in FIG. 17;

[0024]FIG. 19 is a side schematic view of an inflatable heat transferelement according to an embodiment of the invention, as the same isdisposed within a blood vessel;

[0025]FIG. 20 illustrates an inflatable turbulence-inducing heattransfer element according to an alternative embodiment of the inventionemploying a surface area enhancing taper and a turbulence-inducingshape;

[0026]FIG. 21 illustrates a tapered joint which may be employed in theembodiment of FIG. 16;

[0027]FIG. 22 illustrates a turbulence-inducing heat transfer elementaccording to a second alternative embodiment of the invention employinga surface area enhancing taper and turbulence-inducing surface features;

[0028]FIG. 23 illustrates a spiral type of turbulence-inducing surfacefeature which may be employed in the heat transfer element of theembodiment of FIG. 22;

[0029]FIG. 24 illustrates a heat transfer element according to analternative embodiment of the invention employing a surface areaenhancing taper;

[0030]FIG. 25 is a perspective view of a further embodiment of thedevice of the present invention in place in a blood vessel of a patient;

[0031]FIG. 26 is another perspective view of the device shown in FIG.25, with additional details of construction;

[0032]FIG. 27 is a transverse section view of the device shown in FIG.26, along the section line 27-27;

[0033]FIG. 28 is a partial longitudinal section view of the device shownin FIG. 25, showing the flow path of the cooling fluid;

[0034]FIG. 29 is a perspective view of a console system including acirculation set constructed in accordance with an embodiment of theinvention;

[0035]FIG. 30 is a schematic diagram of a circulation set according toan embodiment of the invention;

[0036]FIG. 31 shows a system that may be used to implement a predictivetemperature algorithm;

[0037]FIG. 32 shows a junction between a heat transfer element and acatheter showing position of a catheter-mounted heat transfer element;

[0038]FIG. 33 shows a heat transfer element and catheter showingposition of a distal tip catheter-mounted temperature sensor.

[0039]FIG. 34 shows a pump duty cycle;

[0040]FIG. 35 shows two pump duty cycles and the achievement of a higherduty cycle, compared to that of FIG. 34, when a predictive temperaturealgorithm is employed;

[0041]FIG. 36 shows one graphical method of predicting a controltemperature;

[0042]FIG. 37 shows the relationship of the ratio of areas, beforemeasurement and after measurement, with respect to time;

[0043]FIG. 38 shows another method of predicting a control temperature;

[0044]FIG. 39 shows a system that may implement a method of predictingcontrol temperatures;

[0045]FIG. 40 shows a graph of the areas of, e.g., FIG. 37;

[0046]FIG. 41 shows another system for implementing a method ofpredicting control temperatures;

[0047]FIG. 42 shows a comparator switch which may be used in theembodiment of, e.g., FIG. 41;

[0048]FIG. 43 is a flowchart showing an exemplary method of theinvention employing heating blankets and thermoregulatory drugs;

DETAILED DESCRIPTION

[0049] Overview

[0050] In the following description, the term “pressure communication”is used to describe a situation between two points in a flow or in astanding or flowing fluid. If pressure is applied at one point, thesecond point will eventually feel effects of the pressure if the twopoints are in pressure communication. Any number of valves or elementsmay be disposed between the two points, and the two points may still bein pressure communication if the above test is met. For example, for astanding fluid in a pipe, any number of pipe fittings may be disposedbetween two pipes and, so long as an open path is maintained, points inthe respective pipes may still be in pressure communication.

[0051] A device may be employed to intravascularly lower the temperatureof a body in order to cause therapeutic hypothermia. A cooling elementmay be placed in a high-flow vein such as the vena cavae to absorb heatfrom the blood flowing into the heart. This transfer of heat causes acooling of the blood flowing through the heart and thus throughout thevasculature. Such a method and device may therapeutically be used toinduce, and reverse, an artificial state of hypothermia.

[0052] A heat transfer element that systemically cools blood should becapable of providing the necessary heat transfer rate to produce thedesired cooling effect throughout the vasculature. This may be up to orgreater than 300 watts, and is at least partially dependent on the massof the patient and the rate of blood flow. Surface features may beemployed on the heat transfer element or as part of the heat transferelement to enhance the heat transfer rate. The surface features andother components of the heat transfer element are described in moredetail below.

[0053] One problem with hypothermia as a therapy is that the patient'sthermoregulatory defenses initiate, attempting to defeat thehypothermia. Methods and devices may be used to lessen thethermoregulatory response. For example, a heating blanket may cover thepatient. In this way, the patient may be made more comfortable.Thermoregulatory drugs may also be employed to lower the trigger pointat which the patient's thermoregulatory system begins to initiatedefenses. Such drugs are described in more detail below. A methodemploying thermoregulatory drugs, heating blankets, and heat transferelements is also disclosed below.

[0054] Anatomical Placement

[0055] The internal jugular vein is the vein that directly drains thebrain. The external jugular joins the internal jugular at the base ofthe neck. The internal jugular veins join the subclavian veins to formthe brachiocephalic veins that in turn drain into the superior venacava. The superior vena cava drains into the right atrium of the heartas may be seen by referring ahead to FIG. 1. The superior vena cavasupplies blood to the heart from the upper part of the body.

[0056] A cooling element 102 may be placed into the superior vena cava110, inferior vena cava 110′, or otherwise into a vein which feeds intothe superior vena cava, inferior vena cava, or otherwise into the heartto cool the body. A physician percutaneously places the catheter intothe subclavian or internal or external jugular veins to access thesuperior vena cava. A physician percutaneously places the catheter intothe femoral vein to access the inferior vena cava. The blood, cooled bythe heat transfer element, may be processed by the heart and provided tothe body in oxygenated form to be used as a conductive medium to coolthe body. The lungs have a fairly low heat capacity, and thus the lungsdo not cause appreciable rewarming of the flowing blood.

[0057] Heat Transfer

[0058] When a heat transfer element is inserted into an artery or vein,the primary mechanism of heat transfer between the surface of the heattransfer element and the blood is forced convection.

[0059] Convection relies upon the movement of fluid to transfer heat.Forced convection results when an external force causes motion withinthe fluid. In the case of arterial or venous flow, the beating heartcauses the motion of the blood around the heat transfer element. Themagnitude of the heat transfer rate is proportional to the surface areaof the heat transfer element, the temperature differential, and the heattransfer coefficient of the heat transfer element.

[0060] The receiving artery or vein into which the heat transfer elementis placed has a limited diameter and length. Thus, the surface area ofthe heat transfer element must be limited to avoid significantobstruction of the artery or vein and to allow the heat transfer elementto easily pass through the vascular system. For placement within thesuperior vena cava via the external jugular, the cross sectionaldiameter of the heat transfer element may be limited to about 5-6 mm,and its length may be limited to approximately 10-15 cm. For placementwithin the inferior vena cava, the cross sectional diameter of the heattransfer element may be limited to about 6-7 mm, and its length may belimited to approximately 25-35 cm.

[0061] Decreasing the surface temperature of the heat transfer elementcan increase the temperature differential. However, the minimumallowable surface temperature is limited by the characteristics ofblood. Blood freezes at approximately 0° C. When the blood approachesfreezing, ice emboli may form in the blood, which may lodge downstream,causing serious ischemic injury. Furthermore, reducing the temperatureof the blood also increases its viscosity, which results in a smalldecrease in the value of the convection heat transfer coefficient. Inaddition, increased viscosity of the blood may result in an increase inthe pressure drop within the vessel, thus compromising the flow of bloodto the brain. Given the above constraints, it may be advantageous tolimit the minimum allowable surface temperature of the cooling elementto approximately 5° C. This results in a maximum temperaturedifferential between the blood stream and the cooling element ofapproximately 32° C. For other physiological reasons, there are limitson the maximum allowable surface temperature of the warming element.

[0062] The mechanisms by which the value of the convection heat transfercoefficient may be increased are complex. However, it is well known thatthe convection heat transfer coefficient increases with the level of“mixing” or “turbulent” kinetic energy in the fluid flow. Thus it may beadvantageous to have blood flow with a high degree of mixing in contactwith the heat transfer element.

[0063] The blood flow has a considerably more stable flux in thesuperior or inferior vena cava than in an artery. However, the bloodflow in the superior vena cava still has a high degree of inherentmixing or turbulence. Reynolds numbers in the superior vena cava mayrange, for example, from 2,000 to 5,000. Thus, blood cooling in the venacava may benefit from enhancing the level of mixing with the heattransfer element but this benefit may be substantially less than thatcaused by the inherent mixing.

[0064] A thin boundary layer has been shown to form during the cardiaccycle. Boundary layers develop adjacent to the heat transfer element aswell as next to the walls of the artery or vein. Each of these boundarylayers has approximately the same thickness as the boundary layer thatwould have developed at the wall of the artery in the absence of theheat transfer element. The free stream flow region is developed in anannular ring around the heat transfer element. The heat transfer elementused in such a vessel should reduce the formation of such viscousboundary layers.

[0065] Heat Transfer Element Characteristics

[0066] The intravascular heat transfer element should be flexible inorder to be placed within the vena cavae or other veins or arteries. Theflexibility of the heat transfer element is an important characteristicbecause the same is typically inserted into a vein such as the externaljugular and accesses the superior vena cava by initially passing thougha series of one or more branches. Further, the heat transfer element isideally constructed from a highly thermally conductive material such asmetal or a thin polymer or a doped polymer in order to facilitate heattransfer. The use of a highly thermally conductive material increasesthe heat transfer rate for a given temperature differential between theworking fluid within the heat transfer element and the blood. Thisfacilitates the use of a higher temperature coolant, or lowertemperature warming fluid, within the heat transfer element, allowingsafer working fluids, such as water or saline, to be used. Highlythermally conductive materials, such as metals, tend to be rigid.Therefore, the design of the heat transfer element should facilitateflexibility in an inherently inflexible material.

[0067] It is estimated that the cooling element should absorb at leastabout 300 Watts of heat when placed in the superior vena cava to lowerthe temperature of the body to between about 30° C. and 34° C. Thesetemperatures are thought to be appropriate to obtain the benefits ofhypothermia described above. The power removed determines how quicklythe target temperature can be reached. For example, in a stroke therapyin which it is desired to lower brain temperature, the same may belowered about 4° C. per hour in a 70 kg human upon removal of 300 Watts.

[0068] One embodiment of the invention uses a modular design. Thisdesign creates helical blood flow and produces a level of mixing in theblood flow by periodically forcing abrupt changes in the direction ofthe helical blood flow. The abrupt changes in flow direction areachieved through the use of a series of two or more heat transfersegments, each including one or more helical ridges. The use of periodicabrupt changes in the helical direction of the blood flow in order toinduce strong free stream turbulence may be illustrated with referenceto a common clothes washing machine. The rotor of a washing machinespins initially in one direction causing laminar flow. When the rotorabruptly reverses direction, significant turbulent kinetic energy iscreated within the entire washbasin as the changing currents causerandom turbulent motion within the clothes-water slurry. These surfacefeatures also tend to increase the surface area of the heat transferelement, further enhancing heat transfer.

[0069] A heat transfer element with a smooth exterior surface may beable to provide the desired amount of heat transfer. However, as notedabove, it is well known that the convection heat transfer coefficientincreases with the level of turbulent kinetic energy in the fluid flow.Thus, if flow past a smooth heat transfer element will not transfersufficient heat, it is advantageous to have turbulent or otherwise mixedblood flow in contact with the heat transfer element.

[0070] As noted above, the helical designs create helical blood flow andproduce a high level of mixing in the free stream. For a swirling flowin a tube in which the azimuthal velocity of the fluid vanishes towardthe stationary outer boundary, any non-vanishing azimuthal velocity inthe interior of the flow will result in an instability in which theinner fluid is spontaneously exchanged with fluid near the wall,analogous to Taylor cells in the purely azimuthal flow between arotating inner cylinder and stationary outer cylinder. This instabilityresults from the lack of any force in opposition to the centripetalacceleration of the fluid particles moving along helical paths, thepressure in the tube being a function only of longitudinal position.

[0071] In one embodiment, the device of the present invention imparts anazimuthal velocity to the interior of a developed pipe flow, with thenet result being a continuous exchange of fluid between the core andperimeter of the flow as it moves longitudinally down the pipe. Thisfluid exchange enhances the transport of heat, effectively increasingthe convective heat transfer coefficient over that which would haveobtained in undisturbed pipe flow. This bulk exchange of fluid is notnecessarily turbulent, although turbulence is possible if the inducedazimuthal velocity is sufficiently high.

[0072]FIG. 2 is a perspective view of a mixing-inducing heat transferelement within an artery or vein. In this embodiment, turbulence ormixing is further enhanced by periodically forcing abrupt changes in thedirection of the helical blood flow. Turbulent or mixed flow would befound at point 120, in the free stream area. The abrupt changes in flowdirection are achieved through the use of a series of two or more heattransfer segments, each comprised of one or more helical ridges.Ideally, the segments will be close enough together to preventre-laminarization of the flow in between segments.

[0073] A device according to an embodiment of the invention foraccomplishing such cooling or heating is shown schematically in FIG. 3,which shows a vessel wall 132 in which a blood flow 122 is passing. Acatheter 130 is disposed within the blood flow 122 to affect the bloodtemperature. Catheter 130 has an inlet lumen 126 for providing a workingfluid 128 and an outlet lumen 124 for draining the working fluid 128.The functions of the respective lumens may of course be opposite to thatstated.

[0074] Heat transfer in this system is governed by the followingmechanisms:

[0075] (1) convective heat transfer from the blood 122 to the outletlumen 124;

[0076] (2) conduction through the wall of the outlet lumen 124;

[0077] (3) convective heat transfer from the outlet lumen 124 to theworking fluid 128;

[0078] (4) conduction through the working fluid 128;

[0079] (5) convective heat transfer from working fluid 128 in the outletlumen 124 to the inlet lumen 126; and

[0080] (6) conduction through the wall of the inlet lumen 126.

[0081] Once the materials for the lumens and the working fluid arechosen, the conductive heat transfers are solely dependent on thetemperature gradients. Convective heat transfers, by contrast, also relyon the movement of fluid to transfer heat. Forced convection resultswhen the heat transfer surface is in contact with a fluid whose motionis induced (or forced) by a pressure gradient, area variation, or othersuch force. In the case of blood flow, the beating heart provides anoscillatory pressure gradient to force the motion of the blood incontact with the heat transfer surface. One of the aspects of the deviceuses mixing or turbulence to enhance this forced convective heattransfer.

[0082] The rate of convective heat transfer Q is proportional to theproduct of S, the area of the heat transfer element in direct contactwith the fluid, ΔT=T_(b)−T_(s), the temperature differential between thesurface temperature T_(s) of the heat transfer element and the freestream blood temperature T_(b), and {overscore (h_(c))}, the averageconvection heat transfer coefficient over the heat transfer area.{overscore (h_(c))} is sometimes called the “surface coefficient of heattransfer” or the “convection heat transfer coefficient”.

[0083] The magnitude of the heat transfer rate Q to or from the fluidflow can be increased through manipulation of the above threeparameters. Practical constraints limit the value of these parametersand how much they can be manipulated. For example, the internal diameterof the common carotid artery ranges from 6 to 8 mm. Thus, the heattransfer element residing therein may not be much larger than 4 mm indiameter to avoid occluding the vessel. The length of the heat transferelement should also be limited. For placement within the internal andcommon carotid artery, the length of the heat transfer element islimited to about 10 cm. This estimate is based on the length of thecommon carotid artery, which ranges from 8 to 12 cm. Embodimentsintended for use in the venous system would be analyzed similarly. Forthese venous systems, catheter sizes may be, e.g., 9 French, 10.7French, 14 French, etc.

[0084] Consequently, the value of the surface area S is limited by thephysical constraints imposed by the size of the vessel into which thedevice is placed. Surface features, such as fins, can be used toincrease the surface area of the heat transfer element, however, thesefeatures alone generally cannot usually provide enough surface areaenhancement to meet the required heat transfer rate.

[0085] An embodiment of the device described below provides a taperedheat transfer element which employs a large surface area but which mayadvantageously fit into small arteries and veins. As the device isinflatable, the same may be inserted in relatively small arteries andveins in a deflated state, allowing a minimally invasive entry. When thedevice is in position, the same may be inflated, allowing a largesurface area and thus an enhanced heat transfer rate.

[0086] One may also attempt to vary the magnitude of the heat transferrate by varying ΔT. The value of ΔT=T_(b)−T_(s) can be varied by varyingthe surface temperature T_(s) of the heat transfer element. Theallowable surface temperature of the heat transfer element is limited bythe characteristics of blood. The blood temperature is fixed at about37° C., and blood freezes at approximately 0° C. When the bloodapproaches freezing, ice emboli may form in the blood which may lodgedownstream, causing serious ischemic injury. Furthermore, reducing thetemperature of the blood also increases its viscosity which results in asmall decrease in the value of {overscore (h_(c))}. Increased viscosityof the blood may further result in an increase in the pressure dropwithin the vessel, thus compromising the flow of blood. Given the aboveconstraints, it may be advantageous to limit the surface temperature ofthe heat transfer element to approximately 1° C.-5° C., thus resultingin a maximum temperature differential between the blood stream and theheat transfer element of approximately 32° C.-36° C.

[0087] One may also attempt to vary the magnitude of the heat transferrate by varying {overscore (h_(c))}. Fewer constraints are imposed onthe value of the convection heat transfer coefficient {overscore(h_(c))}. The mechanisms by which the value of {overscore (h_(c))} maybe increased are complex. However, one way to increase {overscore(h_(c))} for a fixed mean value of the velocity is to increase the levelof turbulent kinetic energy in the fluid flow.

[0088] The heat transfer rate Q_(no-flow) in the absence of fluid flowis proportional to ΔT, the temperature differential between the surfacetemperature T_(s) of the heat transfer element and the free stream bloodtemperature T_(b) times k, the diffusion constant, and is inverselyproportion to δ, the thickness of the boundary layer.

[0089] The magnitude of the enhancement in heat transfer by fluid flowcan be estimated by taking the ratio of the heat transfer rate withfluid flow to the heat transfer rate in the absence of fluid flowN=Q_(flow)/Q_(no-flow)={overscore (h_(c))}/(k/δ). This ratio is calledthe Nusselt number (“Nu”). For convective heat transfer between bloodand the surface of the heat transfer element, Nusselt numbers of 30-80have been found to be appropriate for selective cooling applications ofvarious organs in the human body. Nusselt numbers are generallydependent on several other numbers: the Reynolds number, the Womersleynumber, and the Prandtl number.

[0090] Stirring-type mechanisms, which abruptly change the direction ofvelocity vectors, may be utilized to induce turbulent kinetic energy andincrease the heat transfer rate. The level of turbulence so created ischaracterized by the turbulence intensity θ. Turbulence intensity θ isdefined as the root mean square of the fluctuating velocity divided bythe mean velocity. Such mechanisms can create high levels of turbulenceintensity in the free stream, thereby increasing the heat transfer rate.For arterial applications, this turbulence intensity should ideally besustained for a significant portion of the cardiac cycle, and shouldideally be created throughout the free stream and not just in theboundary layer.

[0091] One type of turbulence-inducing heat transfer element which maybe advantageously employed to provide heating or cooling is described inU.S. Pat. No. 6,096,068 to Dobak and Lasheras for a “Selective OrganCooling Catheter and Method of Using the Same,” incorporated byreference above. In that application, the heat transfer element is madeof a high thermal conductivity material, such as metal. The metal heattransfer element provides a high degree of heat transfer due to its highthermal conductivity. In that application, bellows provided a highdegree of articulation that compensated for the intrinsic stiffness ofthe metal. The device size was minimized, e.g., less than 4 mm, toprevent blockage of the blood flowing in the vessel.

[0092]FIG. 4 illustrates the dependency of the Nusselt number on theReynolds number for a fluid flowing through a long duct, i.e., airflowing though a long heated pipe at a uniform wall temperature.Although FIG. 4 illustrates this relationship for a different fluidthrough a different structure, the inventors of the present inventionbelieve a similar relationship exists for blood flow through a bloodvessel. FIG. 4 illustrates that flow is laminar when the Reynolds numberis below some number, in this case about 2100. In the range of Reynoldsnumbers between another set of numbers, in this case 2100 and 10,000, atransition from laminar to turbulent flow takes place. The flow in thisregime is called transitional. The mixing caused by the heat transferelement of the present invention produces a flow that is at leasttransitional. At another Reynolds number, in the case above, about10,000, the flow becomes fully turbulent.

[0093] The type of flow that occurs is important because in laminar flowthrough a duct, there is no mixing of warmer and colder fluid particlesby eddy motion. Thus, the only heat transfer that takes place is throughconduction. Since most fluids have small thermal conductivities, theheat transfer coefficients in laminar flow are relatively small. Intransitional and turbulent flow, mixing occurs through eddies that carrywarmer fluid into cooler regions and vice versa. Since the mixingmotion, even if it is only on a small scale compared to fully turbulentflow, accelerates the transfer of heat considerably, a marked increasein the heat transfer coefficient occurs above a certain Reynolds number,which in the graph of FIG. 4 is about 2100. It can be seen from FIG. 4that it is at approximately this point where the Nusselt numberincreases more dramatically. A different set of numbers may be measuredfor blood flow through an artery or vein. However, the inventors believethat a Nusselt number at least in the transitional region may beimportant for enhanced heat transfer.

[0094] Device

[0095]FIG. 5 is an elevation view of one embodiment of a cooling element102 according to the present invention. The heat transfer element 102includes a series of elongated, articulated segments or modules134,104,106. Three such segments are shown in this embodiment, but twoor more such segments could be used without departing from the spirit ofthe invention. As seen in FIG. 5, a first elongated heat transfersegment 134 is located at the proximal end of the heat transfer element102. A mixing-inducing exterior surface of the segment 134 includes fourparallel helical ridges 138 with four parallel helical grooves 136therebetween. One, two, three, or more parallel helical ridges 138 couldalso be used without departing from the spirit of the present invention.In this embodiment, the helical ridges 138 and the helical grooves 136of the heat transfer segment 134 have a left hand twist, referred toherein as a counter-clockwise spiral or helical rotation, as theyproceed toward the distal end of the heat transfer segment 134.

[0096] The first heat transfer segment 134 is coupled to a secondelongated heat transfer segment 104 by a first bellows section 140,which provides flexibility and compressibility. The second heat transfersegment 104 includes one or more helical ridges 144 with one or morehelical grooves 142 therebetween. The ridges 144 and grooves 142 have aright hand, or clockwise, twist as they proceed toward the distal end ofthe heat transfer segment 104. The second heat transfer segment 104 iscoupled to a third elongated heat transfer segment 106 by a secondbellows section 108. The third heat transfer segment 106 includes one ormore helical ridges 148 with one or more helical grooves 146therebetween. The helical ridge 148 and the helical groove 146 have aleft hand, or counter-clockwise, twist as they proceed toward the distalend of the heat transfer segment 106. Thus, successive heat transfersegments 134, 104, 106 of the heat transfer element 102 alternatebetween having clockwise and counterclockwise helical twists. The actualleft or right hand twist of any particular segment is immaterial, aslong as adjacent segments have opposite helical twist.

[0097] In addition, the rounded contours of the ridges 138, 144, 148allow the heat transfer element 102 to maintain a relatively atraumaticprofile, thereby minimizing the possibility of damage to the bloodvessel wall. A heat transfer element according to the present inventionmay include two, three, or more heat transfer segments.

[0098] The bellows sections 140, 108 are formed from seamless andnonporous materials, such as metal, and therefore are impermeable togas, which can be particularly important, depending on the type ofworking fluid that is cycled through the heat transfer element 102. Thestructure of the bellows sections 140, 108 allows them to bend, extendand compress, which increases the flexibility of the heat transferelement 102 so that it is more readily able to navigate through bloodvessels. The bellows sections 140, 108 also provide for axialcompression of the heat transfer element 102, which can limit the traumawhen the distal end of the heat transfer element 102 abuts a bloodvessel wall. The bellows sections 140, 108 are also able to toleratecryogenic temperatures without a loss of performance. In alternativeembodiments, the bellows may be replaced by flexible polymer tubes,which are bonded between adjacent heat transfer segments.

[0099] The exterior surfaces of the heat transfer element 102 can bemade from metal, and may include very high thermal conductivitymaterials such as nickel, thereby facilitating heat transfer.Alternatively, other metals such as stainless steel, titanium, aluminum,silver, copper and the like, can be used, with or without an appropriatecoating or treatment to enhance biocompatibility or inhibit clotformation. Suitable biocompatible coatings include, e.g., gold, platinumor polymer paralyene. The heat transfer element 102 may be manufacturedby plating a thin layer of metal on a mandrel that has the appropriatepattern. In this way, the heat transfer element 102 may be manufacturedinexpensively in large quantities, which is an important feature in adisposable medical device.

[0100] Because the heat transfer element 102 may dwell within the bloodvessel for extended periods of time, such as 24-48 hours or even longer,it may be desirable to treat the surfaces of the heat transfer element102 to avoid clot formation. In particular, one may wish to treat thebellows sections 140, 108 because stagnation of the blood flow may occurin the convolutions, thus allowing clots to form and cling to thesurface to form a thrombus. One means by which to prevent thrombusformation is to bind an antithrombogenic agent to the surface of theheat transfer element 102. For example, heparin is known to inhibit clotformation and is also known to be useful as a biocoating. Alternatively,the surfaces of the heat transfer element 102 may be bombarded with ionssuch as nitrogen. Bombardment with nitrogen can harden and smooth thesurface and thus prevent adherence of clotting factors. Another coatingthat provides beneficial properties may be a lubricious coating.Lubricious coatings, on both the heat transfer element and itsassociated catheter, allow for easier placement in the, e.g., vena cava.

[0101]FIG. 6 is a longitudinal sectional view of the heat transferelement 102 of an embodiment of the invention, taken along line 6-6 inFIG. 5. Some interior contours are omitted for purposes of clarity. Aninner tube 150 creates an inner lumen 158 and an outer lumen 156 withinthe heat transfer element 102. Once the heat transfer element 102 is inplace in the blood vessel, a working fluid such as saline or otheraqueous solution may be circulated through the heat transfer element102. Fluid flows from a source into the inner lumen 158. At the distalend of the heat transfer element 102, the working fluid exits the innerlumen 158 and enters the outer lumen 156. As the working fluid flowsthrough the outer lumen 156, heat is transferred between the workingfluid and the exterior surface 152 of the heat transfer element 102.Because the heat transfer element 102 is constructed from a highconductivity material, the temperature of its exterior surface 152 mayreach very close to the temperature of the working fluid. The tube 150may be formed as an insulating divider to thermally separate the innerlumen 158 from the outer lumen 156. For example, insulation may beachieved by creating longitudinal air channels in the wall of theinsulating tube 150. Alternatively, the tube 150 may be constructed of anon-thermally conductive material like polytetrafluoroethylene oranother polymer.

[0102] It is important to note that the same mechanisms that govern theheat transfer rate between the exterior surface 152 of the heat transferelement 102 and the blood also govern the heat transfer rate between theworking fluid and the interior surface 154 of the heat transfer element102. The heat transfer characteristics of the interior surface 154 areparticularly important when using water, saline or other fluid thatremains a liquid as the working fluid. Other coolants such as Freonundergo nucleate boiling and create mixing through a differentmechanism. Saline is a safe working fluid, because it is non-toxic, andleakage of saline does not result in a gas embolism, which could occurwith the use of boiling refrigerants. Since mixing in the working fluidis enhanced by the shape of the interior surface 154 of the heattransfer element 102, the working fluid can be delivered to the coolingelement 102 at a warmer temperature and still achieve the necessarycooling rate. Similarly, since mixing in the working fluid is enhancedby the shape of the interior surface of the heat transfer element, theworking fluid can be delivered to the warming element 102 at a coolertemperature and still achieve the necessary warming rate.

[0103] This has a number of beneficial implications in the need forinsulation along the catheter shaft length. Due to the decreased needfor insulation, the catheter shaft diameter can be made smaller. Theenhanced heat transfer characteristics of the interior surface of theheat transfer element 102 also allow the working fluid to be deliveredto the heat transfer element 102 at lower flow rates and lowerpressures. High pressures may make the heat transfer element stiff andcause it to push against the wall of the blood vessel, thereby shieldingpart of the exterior surface 152 of the heat transfer element 102 fromthe blood. Because of the increased heat transfer characteristicsachieved by the alternating helical ridges 138, 144, 148, the pressureof the working fluid may be as low as 5 atmospheres, 3 atmospheres, 2atmospheres or even less than 1 atmosphere.

[0104]FIG. 7 is a transverse sectional view of the heat transfer element102 of the invention, taken at a location denoted by the line 7-7 inFIG. 5. FIG. 7 illustrates a five-lobed embodiment, whereas FIG. 5illustrates a four-lobed embodiment. As mentioned earlier, any number oflobes might be used. In FIG. 7, the construction of the heat transferelement 102 is clearly shown. The inner lumen 158 is defined by theinsulating tube 150. The outer lumen 156 is defined by the exteriorsurface of the insulating tube 150 and the interior surface 154 of theheat transfer element 102. In addition, the helical ridges 144 andhelical grooves 142 may be seen in FIG. 7. Although FIG. 7 shows fiveridges and five grooves, the number of ridges and grooves may vary.Thus, heat transfer elements with 1, 2, 3, 4, 5, 6, 7, 8 or more ridgesare specifically contemplated.

[0105]FIG. 8 is a perspective view of a heat transfer element 102 in usewithin a blood vessel, showing only one helical lobe per segment forpurposes of clarity. Beginning from the proximal end of the heattransfer element (not shown in FIG. 8), as the blood moves forward, thefirst helical heat transfer segment 104 induces a counter-clockwiserotational inertia to the blood. As the blood reaches the second segment104, the rotational direction of the inertia is reversed, causing mixingwithin the blood. Further, as the blood reaches the third segment 106,the rotational direction of the fluid is again reversed. The suddenchanges in flow direction actively reorient and randomize the velocityvectors, thus ensuring mixing throughout the bloodstream. During suchmixing, the velocity vectors of the blood become more random and, insome cases, become perpendicular to the axis of the vessel. Thus, alarge portion of the volume of warm blood in the vessel is activelybrought in contact with the heat transfer element 102 where it can becooled by direct contact rather than being cooled largely by conductionthrough adjacent laminar layers of blood.

[0106] Referring back to FIG. 5, the heat transfer element 102 has beendesigned to address all of the design criteria discussed above. The heattransfer element 102 is flexible and is made of a highly conductivematerial. The flexibility is provided by a segmental distribution ofbellows sections 140, 108 that provide an articulating mechanism.Bellows have a known convoluted design that provide flexibility. Theridges allow the heat transfer element 102 to maintain a relativelyatraumatic profile, thereby minimizing the possibility of damage to thevessel wall. The heat transfer element 102 has been designed to promotemixing both internally and externally. The modular or segmental designallows the direction of the grooves to be reversed between segments. Thealternating helical rotations create an alternating flow that results inmixing the blood in a manner analogous to the mixing action created bythe rotor of a washing machine that switches directions back and forth.This action is intended to promote mixing to enhance the heat transferrate. The alternating helical design also causes beneficial mixing, orturbulent kinetic energy, of the working fluid flowing internally.

[0107]FIG. 9 is a perspective view of a third embodiment of a heattransfer element 160 according to the present invention. The heattransfer element 160 is comprised of a series of elongated, articulatedsegments or modules 162. A first elongated heat transfer segment 162 islocated at the proximal end of the heat transfer element 160. Thesegment 162 may be a smooth right circular cylinder (not shown), or itcan incorporate a turbulence-inducing or mixing-inducing exteriorsurface. The turbulence-inducing or mixing-inducing exterior surfaceshown on the segment 162 in FIG. 16 comprises a plurality of parallellongitudinal ridges 164 with parallel longitudinal grooves 168therebetween. One, two, three, or more parallel longitudinal ridges 164could be used without departing from the spirit of the presentinvention. In the embodiment where they are used, the longitudinalridges 164 and the longitudinal grooves 168 of the heat transfer segment162 are aligned parallel with the axis of the first heat transfersegment 162.

[0108] The first heat transfer segment 162 is coupled to a secondelongated heat transfer segment 162 by a first flexible section such asa bellows section 166, which provides flexibility and compressibility.Alternatively, the flexible section may be a simple flexible tube, verysimilar to a smooth heat transfer segment, but flexible. The second heattransfer segment 162 also comprises a plurality of parallel longitudinalridges 164 with parallel longitudinal grooves 168 therebetween. Thelongitudinal ridges 164 and the longitudinal grooves 168 of the secondheat transfer segment 162 are aligned parallel with the axis of thesecond heat transfer segment 162. The second heat transfer segment 162is coupled to a third elongated heat transfer segment 162 by a secondflexible section such as a bellows section 166 or a flexible tube. Thethird heat transfer segment 162 also comprises a plurality of parallellongitudinal ridges 164 with parallel longitudinal grooves 168therebetween. The longitudinal ridges 164 and the longitudinal grooves168 of the third heat transfer segment 162 are aligned parallel with theaxis of the third heat transfer segment 162. Further, in thisembodiment, adjacent heat transfer segments 162 of the heat transferelement 160 have their longitudinal ridges 164 aligned with each other,and their longitudinal grooves 168 aligned with each other. Offsettingof the longitudinal ridges and the longitudinal grooves from each otheron adjacent segments promotes turbulence or mixing in blood flowing pastthe exterior of the heat transfer element 170. In other embodiments,they may be offset.

[0109] In addition, the rounded contours of the ridges 164 also allowthe heat transfer element 160 to maintain a relatively atraumaticprofile, thereby minimizing the possibility of damage to the bloodvessel wall. A heat transfer element 160 according to the presentinvention may be comprised of two, three, or more heat transfer segments162.

[0110]FIG. 10 is a transverse section view of a heat transfer segment180, illustrative of segment 162 of heat transfer element 160 shown inFIG. 9. The coaxial construction of the heat transfer segment 180 isclearly shown. The inner coaxial lumen 182 is defined by the insulatingcoaxial tube 184. The outer lumen 190 is defined by the exterior surfaceof the insulating coaxial tube 184 and the interior surface 192 of theheat transfer segment 180. In addition, parallel longitudinal ridges 186and parallel longitudinal grooves 188 may be seen in FIG. 10. Thelongitudinal ridges 186 and the longitudinal grooves 188 may have arelatively rectangular cross-section, as shown in FIG. 10, or they maybe more triangular in cross-section, as shown in FIG. 9. Thelongitudinal ridges 186 and the longitudinal grooves 188 may be formedonly on the exterior surface of the segment 180, with a cylindricalinterior surface 192. Alternatively, corresponding longitudinal ridgesand grooves may be formed on the interior surface 192 as shown, topromote turbulence or mixing in the working fluid. Although FIG. 10shows six ridges and six grooves, the number of ridges and grooves mayvary. Where a smooth exterior surface is desired, the outer tube of theheat transfer segment 180 could have smooth outer and inner surfaces,like the inner tube 184. Alternatively, the outer tube of the heattransfer segment 180 could have a smooth outer surface and a ridgedinner surface like the interior surface 192 shown in FIG. 10.

[0111]FIG. 11 is a cut-away perspective view of an alternativeembodiment of a heat transfer element 194. An external surface 196 ofthe heat transfer element 194 is covered with a series of axiallystaggered protrusions 198. The staggered nature of the outer protrusions198 is readily seen with reference to FIG. 12 which is a transversecross-sectional view taken at a location denoted by the line 12-12 inFIG. 11. As the blood flows along the external surface 196, it collideswith one of the staggered protrusions 198 and a turbulent wake flow iscreated behind the protrusion. As the blood divides and swirls alongsideof the first staggered protrusion 198, its turbulent wake encountersanother staggered protrusion 198 within its path preventing there-lamination of the flow and creating yet more mixing. In this way, thevelocity vectors are randomized and mixing is created not only in theboundary layer but also throughout a large portion of the free stream.As is the case with the preferred embodiment, this geometry also inducesa mixing effect on the internal working fluid flow.

[0112] A working fluid is circulated up through an inner lumen 200defined by an insulating tube 202 to a distal tip of the heat transferelement 194. The working fluid then traverses an outer lumen 204 inorder to transfer heat to the exterior surface 196 of the heat transferelement 194. The inside surface of the heat transfer element 194 issimilar to the exterior surface 196 in order to induce turbulent or“mixed” flow of the working fluid. The inner protrusions can be alignedwith the outer protrusions 198 as shown in FIG. 12 or they can be offsetfrom the outer protrusions 198 as shown in FIG. 11.

[0113] With reference to FIGS. 13 and 14, a catheter 206 constructed inaccordance with an alternative embodiment of the invention will now bedescribed. The catheter 206 includes an elongated catheter body 208 witha heat transfer element 210 located at a distal portion 212 of thecatheter body 208. The catheter 206 includes a multiple lumenarrangement 214 to deliver fluid to and from an interior 216 of the heattransfer element 210 and allow the catheter 206 to be placed into ablood vessel over a guidewire. The heat transfer element 210 includesturbulence-inducing invaginations 218 located on an exterior surface252. Similar invaginations may be located on an interior surface 220 ofthe heat transfer element 210, but are not shown for clarity. Further,it should be noted that the heat transfer element 210 is shown with onlyfour invaginations 218. Other embodiments may employ multiple elementsconnected by flexible joints or bellows as disclosed above. A singleheat transfer element is shown in FIG. 13 merely for clarity. In analternative embodiment of the invention, any of the other heat-transferelements described herein may replace heat transfer element 212.Alternatively, the multi-lumen arrangement may be used to deliver fluidto and from the interior of an operative element(s) other than aheat-transfer-element such as, but without limitation, a catheterballoon, e.g., a dilatation balloon.

[0114] The catheter 206 includes an integrated elongated multiple lumenmember such as a bi-lumen member 222 having a first lumen member 226 anda second lumen member 228. The bi-lumen member 222 has a substantiallyfigure-eight cross-sectional shape (FIG. 14) and an outer surface 224with the same general shape. The first lumen member 226 includes aninterior surface 230 defining a first lumen or guide wire lumen 232having a substantially circular cross-sectional shape. The interiorsurface 230 may be coated with a lubricious material to facilitate thesliding of the catheter 206 over a guidewire. The first lumen member 226further includes a first exterior surface 242 and a second exteriorsurface 244. The first lumen 232 is adapted to receive a guide wire forplacing the catheter 206 into a blood vessel over the guidewire in awell-known manner.

[0115] In FIGS. 13 and 14, the guide wire lumen 232 is not coaxial withthe catheter body 208. In an alternative embodiment of the invention,the guide wire lumen 232 may be coaxial with the catheter body 208.

[0116] The second lumen member 228 includes a first interior surface 246and a second interior surface 248, which is the same as the secondexterior surface 244 of the first lumen member 226, that together definea second lumen or supply lumen 250 having a substantially luniformcross-sectional shape. The second lumen member 228 further includes anexterior surface 252. The second lumen 250 has a cross-sectional areaA₂. The second lumen 250 is adapted to supply working fluid to theinterior of the heat transfer element 210 to provide temperature controlof a flow or volume of blood in the manner described above.

[0117] The second lumen member 228 terminates short of a distal end 236of the catheter 206, leaving sufficient space for the working fluid toexit the supply lumen 250 so it can contact the interior surface 220 ofthe heat transfer element 210 for heat transfer purposes.

[0118] Although the second lumen member 228 is shown as a single supplylumen terminating adjacent the distal end 236 of catheter 206 to deliverworking fluid at the distal end of the catheter 206, with reference toFIG. 15, in an alternative embodiment of the invention, a single supplylumen member 254 may include one or more outlet openings 256 adjacentthe distal end 236 of the catheter 206 and one or more outlet openings258 adjacent a mid-point along the interior length of the heat transferelement 210. This arrangement improves the heat transfer characteristicsof the heat-transfer element 210 because fresh working fluid at the sametemperature is delivered separately to each segment 104, 106 of theinterior of the heat-transfer element 210 instead of in series.

[0119] Although two heat transfer segments 104, 106 are shown, it willbe readily apparent that a number of heat transfer segments other thantwo, e.g., one, three, four, etc., may be used.

[0120] It will be readily apparent to those skilled in the art that inanother embodiment of the invention, in addition to the one or moreopenings 256 in the distal portion of the heat transfer element 210, oneor more openings at one or more locations may be located anywhere alongthe interior length of the heat transfer element 210 proximal to thedistal portion.

[0121] With reference to FIG. 16, in an alternative embodiment of theinvention, first and second supply lumen members 260, 262 definerespective first and second supply lumens 264, 266 for supplying workingfluid to the interior of the heat transfer element 210. The first supplylumen 260 terminates just short of the distal end 236 of the catheter206 to deliver working fluid at the distal portion of the heat transferelement 210. The second supply lumen 262 terminates short of the distalportion of the catheter 206, for example, at approximately a mid-lengthpoint along the interior of the heat transfer element 210 for deliveringworking fluid to the second heat transfer segment 104. In an alternativeembodiment of the invention, the second lumen member 262 may terminateanywhere along the interior length of the heat transfer element 210proximal to the distal portion of the heat transfer element 210.Further, a number of supply lumens 262 greater than two may terminatealong the interior length of the heat transfer element 210 fordelivering a working fluid at a variety of points along the interiorlength of the heat transfer element 210.

[0122] With reference back to FIGS. 13 and 14, the bi-lumen member 222is preferably extruded from a material such as polyurethane or Pebax. Inan embodiment of the invention, the bi-lumen member is extrudedsimultaneously with the catheter body 208. In an alternative embodimentof the invention, the first lumen member 226 and second lumen member 228are formed separately and welded or fixed together.

[0123] A third lumen or return lumen 238 provides a convenient returnpath for working fluid. The third lumen 238 is substantially defined bythe interior surface 220 of the heat transfer element 210, an interiorsurface 240 of the catheter body 208, and the exterior surface 224 ofthe bi-lumen member 222. The inventors have determined that the workingfluid pressure drop through the lumens is minimized when the third lumen238 has a hydraulic diameter D₃ that is equal to 0.75 of the hydraulicdiameter D₂ of the second lumen 250. However, the pressure drop thatoccurs when the ratio of the hydraulic diameter D₃ to the hydraulicdiameter D₂ is substantially equal to 0.75, i.e., 0.75±0.10, works well.For flow through a cylinder, the hydraulic diameter D of a lumen isequal to four times the cross-sectional area of the lumen divided by thewetted perimeter. The wetted perimeter is the total perimeter of theregion defined by the intersection of the fluid path through the lumenand a plane perpendicular to the longitudinal axis of the lumen. Thewetted perimeter for the return lumen 238 would include an inner wettedperimeter (due to the outer surface 224 of the bi-lumen member 222) andan outer wetted perimeter (due to the interior surface 240 of thecatheter body 208). The wetted perimeter for the supply lumen 250 wouldinclude only an outer wetted perimeter (due to the first and secondinterior surfaces 246, 248 of the bi-lumen member 222). Thus, the wettedperimeter for a lumen depends on the number of boundary surfaces thatdefine the lumen.

[0124] The third lumen 238 is adapted to return working fluid deliveredto the interior of the heat transfer element 210 back to an externalreservoir or the fluid supply for recirculation in a well-known manner.

[0125] In an alternative embodiment, the third lumen 238 is the supplylumen and the second lumen 250 is the return lumen. Accordingly, it willbe readily understood by the reader that adjectives such as “first,”“second,” etc. are used to facilitate the reader's understanding of theinvention and are not intended to limit the scope of the invention,especially as defined in the claims.

[0126] In a further embodiment of the invention, the member 222 mayinclude a number of lumens other than two such as, for example, 1, 3, 4,5, etc. Additional lumens may be used as additional supply and/or returnlumens, for other instruments, e.g., imaging devices, or for otherpurposes, e.g., inflating a catheter balloon or delivering a drug.

[0127] Heating or cooling efficiency of the heat transfer element 210 isoptimized by maximizing the flow rate of working fluid through thelumens 250, 238 and minimizing the transfer of heat between the workingfluid and the supply lumen member. Working fluid flow rate is maximizedand pressure drop minimized in the present invention by having the ratioof the hydraulic diameter D₃ of the return lumen 238 to the hydraulicdiameter D₂ of the supply lumen 250 equal to 0.75. However, a ratiosubstantially equal to 0.75, i.e., 0.75±10-20%, is acceptable. Heattransfer losses are minimized in the supply lumen 250 by minimizing thesurface area contact made between the bi-lumen member 222 and theworking fluid as it travels through the supply lumen member. The surfacearea of the supply lumen member that the supplied working fluid contactsis much less than that in co-axial or concentric lumens used in the pastbecause the supplied working fluid only contacts the interior of onelumen member compared to contacting the exterior of one lumen member andthe interior of another lumen member. Thus, heat transfer losses areminimized in the embodiments of the supply lumen in the multiple lumenmember 222 of the present invention.

[0128] It will be readily apparent to those skilled in the art that thesupply lumen 250 and the return lumen 238 may have cross-sectionalshapes other than those shown and described herein and still maintainthe desired hydraulic diameter ratio of substantially 0.75. Withreference to FIGS. 17 and 18, an example of a catheter 206 including asupply lumen and a return lumen constructed in accordance with analternative preferred embodiment of the invention, where the hydraulicdiameter ratio of the return lumen to the supply lumen is substantiallyequal to 0.75 is illustrated. It should be noted, the same elements asthose described above with respect to FIGS. 13 and 14 are identifiedwith the same reference numerals and similar elements are identifiedwith the same reference numerals, but with a (′) suffix.

[0129] The catheter 206 illustrated in FIGS. 17 and 18 includes amultiple lumen arrangement 214′ for delivering working fluid to and froman interior 216 of the heat transfer element 210 and allowing thecatheter to be placed into a blood vessel over a guide wire. Themultiple lumen arrangement 214′ includes a bi-lumen member 222′ with aslightly different construction from the bi-lumen member 222 discussedabove with respect to FIGS. 13 and 14. Instead of an outer surface 224that is generally figure eight shaped, the bi-lumen member 222′ has anouter surface 224′ that is circular. Consequently, the third lumen 238′has an annular cross-sectional shape.

[0130] As discussed above, maintaining the hydraulic diameter ratio ofthe return lumen 250′ to the supply lumen 238′ substantially equal to0.75 maximizes the working fluid flow rate through the multiple lumenarrangement 214′.

[0131] In addition, the annular return lumen 238′ enhances theconvective heat transfer coefficient within the heat transfer element210, especially adjacent an intermediate segment or bellows segment 268.Working fluid flowing through the annular return lumen 238′, between theouter surface 224′ of the bi-lumen member 222′ and the inner surface 220of the heat transfer element, encounters a restriction 270 caused by theimpingement of the bellows section 268 into the flow path. Although theimpingement of the bellows section 268 is shown as causing therestriction 270 in the flow path of the return lumen 238′, in analternative embodiment of the invention, the bi-lumen member 222′ maycreate the restriction 270 by being thicker in this longitudinal regionof the bi-lumen member 222′. The distance between the bi-lumen member222′ and the bellows section 268 is such that the characteristic flowresulting from a flow of working fluid is at least of a transitionalnature.

[0132] For a specific working fluid flux or flow rate (cc/sec), the meanfluid velocity through the bellows section restriction 270 will begreater than the mean fluid velocity obtained through the annular returnlumen 238′ in the heat transfer segment 104, 106 of the heat transferelement 210. Sufficiently high velocity through the bellows sectionrestriction 270 will result in wall jets 272 directed into the interiorportion 220 of the heat transfer segment 104. The wall jets 272 enhancethe heat transfer coefficient within the helical heat transfer segment104 because they enhance the mixing of the working fluid along theinterior of the helical heat transfer segment 104. Increasing thevelocity of the jets 272 by increasing the working fluid flow rate ordecreasing the size of the restriction 270 will result in a transitioncloser to the jet exit and greater mean turbulence intensity throughoutthe helical heat transfer segment 104. Thus, the outer surface 224′ ofthe bi-lumen member 222′, adjacent the bellows 268, and the innersurface of the bellows 268 form means for further enhancing the transferof heat between the heat transfer element 210 and the working fluid, inaddition to that caused by the interior portion 220 of the helical heattransfer segment 104.

[0133] In an alternative embodiment of the invention, as describedabove, the heat transfer element may include a number of heat transfersegments other than two, i.e., 1, 3, 4, etc., with a correspondingnumber of intermediate segments, i.e., the number of heat transfersegments minus one.

[0134] The embodiment of the multiple lumen arrangement 222 discussedwith respect to FIGS. 13 and 14 would not enhance the convective heattransfer coefficient as much as the embodiment of the multiple lumenarrangement 222′ discussed with respect to FIGS. 17 and 18 becauseworking fluid would preferentially flow through the larger areas of thereturn lumen 238, adjacent the junction of the first lumen member 226and second lumen member 228. Thus, high-speed working fluid would havemore contact with the outer surface 224 of the bi-lumen member 222 andless contact with the interior portion of 220 heat transfer element 210.In contrast, the annular return lumen 238′ of the multiple lumenarrangement 222′ causes working fluid flow to be axisymmetric so thatsignificant working fluid flow contacts all areas of the helical segmentequally.

[0135] On the other hand, the heat transfer element according to anembodiment of the present invention may also be made of a flexiblematerial, such as latex rubber. The latex rubber provides a high degreeof flexibility which was previously achieved by articulation. The latexrubber further allows the heat transfer element to be made collapsibleso that when deflated the same may be easily inserted into a vessel.Insertion and location may be conveniently made by way of a guidecatheter or guide wire. Following insertion and location in the desiredvessel, the heat transfer element may be inflated for use by a workingfluid such as saline, water, perfluorocarbons, or other suitable fluids.

[0136] A heat transfer element made of a flexible material generally hassignificantly less thermal conductivity than a heat transfer elementmade of metal. The device compensates for this by enhancing the surfacearea available for heat transfer. This may be accomplished in two ways:by increasing the cross-sectional size and by increasing the length.Regarding the former, the device may be structured to be large wheninflated, because when deflated the same may still be inserted into anartery or vein. In fact, the device may be as large as the vessel wall,so long as a path for blood flow is allowed, because the flexibility ofthe device tends to prevent damage to the wall even upon contact. Suchpaths are described below. Regarding the latter, the device may beconfigured to be long. One way to configure a long device is to taperthe same so that the device may fit into distal vessels having reducedradii in a manner described below. The device further compensates forthe reduced thermal conductivity by reducing the thickness of the heattransfer element wall.

[0137] In alternative embodiments, versions of the device use a heattransfer element design that produces a high level of mixing orturbulence in the free stream of the blood and in the working fluid. Oneembodiment of the invention forces a helical motion on the working fluidand imposes a helical barrier in the blood, causing mixing. In analternative embodiment, the helical barrier is tapered. In a secondalternative embodiment, a tapered inflatable heat transfer element has ashape or surface features to cause mixing or turbulence. As one example,the surface features may be a spiral shape. In another example, thesurface features may be staggered protrusions. In all of theseembodiments, the design forces a high level of mixing in the free streamof the blood by causing the blood to navigate a tortuous path whilepassing through the vessel. This tortuous path causes the blood toundergo violent accelerations resulting in turbulence.

[0138] In a third alternative embodiment of the invention, a taper of aninflatable heat transfer element provides enough additional surface areaper se to cause sufficient heat transfer. In all of the embodiments, theinflation is performed by the working fluid, such as water or saline.

[0139] Referring to FIG. 19, a side view is shown of a first embodimentof a heat transfer element 272 according to an embodiment of theinvention. The heat transfer element 272 is formed by an inlet lumen 276and an outlet lumen 274. In this embodiment, the outlet lumen 274 isformed in a helix shape surrounding the inlet lumen 276 that is formedin a pipe shape. The names of the lumens are of course not limiting. Itwill be clear to one skilled in the art that the inlet lumen 276 mayserve as an outlet and the outlet lumen 274 may serve as an inlet. Itwill also be clear that the heat transfer element is capable of bothheating (by delivering heat to) and cooling (by removing heat from) adesired area.

[0140] The heat transfer element 272 is rigid but flexible so as to beinsertable in an appropriate vessel by use of a guide catheter.Alternatively, the heat transfer element may employ a device forthreading a guide wire therethrough to assist placement within anartery. The heat transfer element 272 has an inflated length of L, ahelical diameter of D_(c), a tubal diameter of d, and a helical angle ofα. For example, D_(c) may be about 3.3 mm and d may be about 0.9 mm to 1mm. Of course, the tubal diameter d need not be constant. For example,the diameter of the inlet lumen 276 may differ from that of the outletlumen 272.

[0141] The shape of the outlet lumen 274 in FIG. 19 is helical. Thishelical shape presents a cylindrical obstacle, in cross-section, to theflow of blood. Such obstacles tend to create turbulence in the freestream of blood. In particular, the form of turbulence is the creationof von Karman vortices in the wake of the flow of blood, downstream ofthe cylindrical obstacles.

[0142] Typical inflatable materials are not highly thermally conductive.They are much less conductive than the metallic heat transfer elementdisclosed in the patent incorporated by reference above. The differencein conductivity is compensated for in at least two ways in the presentdevice. The material is made thinner and the heat transfer element isafforded a larger surface area. Regarding the former, the thickness maybe less than about ½ mil for adequate cooling.

[0143] Thin inflatable materials, particularly those with large surfaceareas, may require a structure, such as a wire, within their interiorsto maintain their approximate uninflated positions so that uponinflation, the proper form is achieved. Thus, a wire structure 282 isshown in FIG. 19 that may be advantageously disposed within theinflatable material to perform such a function.

[0144] Another consideration is the angle α of the helix. Angle α shouldbe determined to optimize the helical motion of the blood around thelumens 274 and 276, enhancing heat transfer. Of course, angle α shouldalso be determined to optimize the helical motion of the working fluidwithin the lumens 274 and 276. The helical motion of the working fluidwithin the lumens 274 and 276 increases the turbulence in the workingfluid by creating secondary motions. In particular, helical motion of afluid in a pipe induces two counter-rotating secondary flows.

[0145] An enhancement of {overscore (h_(c))} would be obtained in thissystem, and this enhancement may be described by a Nusselt number Nu ofup to about 10 or even more.

[0146] The above discussion describes one embodiment of a heat transferelement. An alternative embodiment of the device, shown in a side viewin FIG. 20, illustrates a heat transfer element 286 with a surface areaenhancement. Increasing the surface area of the inflatable materialenhances heat transfer. The heat transfer element 272 includes a seriesof coils or helices of different coil diameters and tubal diameters. Itis not strictly necessary that the tubal diameters differ, but it islikely that commercially realizable systems will have differing tubaldiameters. The heat transfer element 272 may taper either continuouslyor segmentally.

[0147] This alternative embodiment enhances surface area in two ways.First, the use of smaller diameter lumens enhances the overallsurface-to-volume ratio. Second, the use of progressively smaller (i.e.,tapered) lumens allows a distal end 312 to be inserted further into anartery than would be possible with the embodiment of FIG. 19.

[0148] In the embodiment of FIG. 20, a first coil segment 288 is shownhaving length L₁ and diameter D_(C1). The first coil segment 288 isformed of an inlet lumen 296 having diameter d₁ and an outlet lumen 298having diameter d₁′. In the first coil segment, as well as the others,the outlet lumen need not immediately drain the inlet lumen. In FIG. 20,the inlet lumen for each segment feeds the inlet lumen of the succeedingsegment except for an inlet lumen adjacent a distal end 312 of the heattransfer element 286 that directly feeds its corresponding outlet lumen.

[0149] A separate embodiment may also be constructed in which the inletlumens each provide working fluid to their corresponding outlet lumens.In this embodiment, either a separate lumen needs to be provided todrain each outlet lumen or each outlet lumen drains into the adjacentoutlet lumen.

[0150] This embodiment has the advantage that an opposite helicity maybe accorded each successive segment. The opposite helicities in turnenhance the turbulence of the working fluid flowing past them.

[0151] A second coil segment 290 is shown having length L₂ and diameterD_(C2). The second coil segment 290 is formed of an inlet lumen 300having diameter d₂ and an outlet lumen 302 having diameter d₂′. A thirdcoil segment 292 is shown having length L₃ and diameter D_(C3). Thethird coil segment 292 is formed of an inlet lumen 304 having diameterd₃ and an outlet lumen 306 having diameter d₃′. Likewise, a fourth coilsegment 294 is shown having length L₄ and diameter D_(C4). The fourthcoil segment 294 is formed of an inlet lumen 308 having diameter d₄ andan outlet lumen 310 having diameter d₄′. The diameters of the lumens,especially that of the lumen located at or near distal end 312, shouldbe large enough to not restrict the flow of the working fluid withinthem. Of course, any number of lumens may be provided depending on therequirements of the user.

[0152]FIG. 21 shows the connection between two adjacent inlet lumens 296and 300. A joint 314 is shown coupling the two lumens. The constructionof the joint may be by way of variations in stress, hardening, etc.

[0153] An advantage to this alternative embodiment arises from thesmaller diameters of the distal segments. The heat transfer element ofFIG. 20 may be placed in smaller workspaces than the heat transferelement of FIG. 19. For example, a treatment for brain trauma mayinclude placement of a cooling device in the internal carotid artery ofa patient. As noted above, the common carotid artery feeds the internalcarotid artery. In some patients, the heat transfer element of FIG. 19may not fit in the internal carotid artery. Similarly, the first coilsegment of the heat transfer element in FIG. 20 may not easily fit inthe internal carotid artery, although the second, third, and fourthsegments may fit. Thus, in the embodiment of FIG. 20, the first coilsegment may remain in the common carotid artery while the segments ofsmaller diameter (the second, third, and fourth) may be placed in theinternal carotid artery. In fact, in this embodiment, D_(C1) may belarge, such as 5-6 mm. The overall length of the heat transfer element286 may be, e.g., about 20 to 25 cm. Of course, such considerations playless of a role when the device is placed in a large vein such as theinferior vena cava.

[0154] An additional advantage was mentioned above. The surface area ofthe alternative embodiment of FIG. 20 may be substantially larger thanthat of the embodiment of FIG. 19, resulting in significantly enhancedheat transfer. For example, the enhancement in surface area may besubstantial, such as up to or even more than three times compared to thesurface area of the device of the application incorporated by referenceabove. An additional advantage of both embodiments is that the helicalrounded shape allows atraumatic insertion into cylindrical cavities suchas, e.g., arteries.

[0155] The embodiment of FIG. 20 may result in an Nu from 1 up to about50.

[0156]FIG. 22 shows a second alternative embodiment of the deviceemploying surface features rather than overall shape to induceturbulence. In particular, FIG. 22 shows a heat transfer element 314having an inlet lumen (not shown) and an outlet inflatable lumen 328having four segments 316, 318, 320, and 330. Segment 346 is adjacent aproximal end 326 and segment 330 is adjacent a distal end 322. Thesegments are arranged having reducing radii in the direction of theproximal end to the distal end. In a manner similar to that of theembodiment of FIG. 28, the feature of reducing radii allows insertion ofthe heat transfer element into small work places such as small arteries.

[0157] Heat transfer element 314 has a number of surface features 324disposed thereon. The surface features 324 may be constructed with,e.g., various hardening treatments applied to the heat transfer element314, or alternatively by injection molding. The hardening treatments mayresult in a wavy or corrugated surface to the exterior of heat transferelement 314. The hardening treatments may further result in a wavy orcorrugated surface to the interior of heat transfer element 314. FIG. 23shows a variation of this embodiment, in which a fabrication process isused which results in a spiral or helical shape to the surface features.

[0158] The embodiment of FIG. 22 may result in an Nu of about 1 to 50.

[0159] Of course, other surface features may also be used which resultin turbulence in fluids flowing past them. These include spirals,helices, protrusions, various polygonal bodies, pyramids, tetrahedrons,wedges, etc.

[0160] In some situations, an enhanced surface area alone, without thecreation of additional turbulence, may result in sufficient heattransfer to cool the blood. Referring to FIG. 24, a heat transferelement 332 is shown having an inlet lumen 334 and an outlet lumen 336.The inlet lumen 334 provides a working fluid to the heat transferelement 332 and outlet lumen 336 drains the working fluid from the same.The functions may, of course, be reversed. The heat transfer element 332is further divided into five segments, although more or less may beprovided as dictated by requirements of the user. The five segments inFIG. 24 are denoted segments 338, 340, 342, 344, and 346. In FIG. 24,the segment 338 has a first and largest radius R₁, followed bycorresponding radii for segments 340, 342, 344, and 346. Segment 346 hasa second and smallest radius. The length of the segment 338 is L₁,followed by corresponding lengths for segments 340, 342, 344, and 346.

[0161] A purely tapered (nonsegmented) form may replace the taperedsegmental form, but the former may be more difficult to manufacture. Ineither case, the tapered form allows the heat transfer element 332 to bedisposed in small arteries, i.e., arteries with radii smaller than R₁. Asufficient surface area is thus afforded even in very small arteries toprovide the required heat transfer.

[0162] The surface area and thus the size of the device should besubstantial to provide the necessary heat transfer. Example dimensionsfor a three-segmented tapered form may be as follows: L₁=10 cm, R₁=2.5mm; L₂=10 cm, R₂=1.65 mm, L₃=5 cm, R₃=1 mm. Such a heat transfer elementwould have an overall length of 25 cm and a surface area of 3×10⁻⁴ m².

[0163] The embodiment of FIG. 24 results in an enhancement of the heattransfer rate of up to about 300% due to the increased surface area Salone.

[0164] A variation of the embodiment of FIG. 24 includes placing atleast one mixing-inducing surface feature within the interior of theoutlet lumen 336. This surface feature may induce mixing in the workingfluid, thereby increasing the convective heat transfer rate in themanner described above.

[0165] Another variation of the embodiment of FIG. 24 involves reducingthe joint diameter between segments (not shown). For example, theinflatable material may be formed such that joints 348, 350, 352, and354 have a diameter only slightly greater than that of the inlet lumen334. In other words, the heat transfer element 332 has a tapered“sausage” shape.

[0166] In all of the embodiments, the inflatable material may be formedfrom seamless and nonporous materials that are therefore impermeable togas. Impermeability can be particularly important depending on the typeof working fluid that is cycled through the heat transfer element. Forexample, the inflatable material may be latex or other such rubbermaterials, or alternatively of any other material with similarproperties under inflation. The flexible material allows the heattransfer element to bend, extend and compress so that it is more readilyable to navigate through tiny blood vessels. The material also providesfor axial compression of the heat transfer element that can limit thetrauma when the distal end of the heat transfer element 272 abuts ablood vessel wall. The material should be chosen to toleratetemperatures in the range of −1° C. to 37° C., or even higher in thecase of blood heating, without a loss of performance.

[0167] It is noted that under pressure the balloons above may have adegree of stiffness. In particular, for a supply lumen pressure p_(s)and outlet pressure p_(o), the balloon pressure p_(b) may be calculatedas follows:

[0168] For a constant catheter flux Q, Q_(supply)=Q_(return):

Δp _(s) =p _(s) −p _(b)

Δp _(r) =p _(b) −p _(o) =p _(b) if we assume p _(o) is zero

[0169] if the supply and return lumens are symmetric in shape and size,then:

Δp_(s)=Δp_(r) and p_(b)=½p_(s)

[0170] If A_(s) is the supply lumen cross-sectional area and A_(r) isthe return lumen cross-sectional area, then if A_(s)=A_(r) the totalpressure drop is minimized if the shapes are equivalent. However, ifA_(s)<A_(r) the total pressure drop increases but Δp_(r)=p_(b) decreasesand the balloon is less stiff. Also if A_(r) were increased relative toA_(s) then the balloon pressure would decrease but the pump pressurep_(s) would increase. In this way, the balloon pressure could bedesirably reduced and flexibility increased, minimizing the probabilityof vessel damage.

EXAMPLE

[0171] For supply and return lumens each of diameter d/4 and mass fluxQ,

Δp _(s) =αQ/d ⁴(256)

Δp _(r) =αQ/d ⁴(256)

And p _(b) =Δp _(r) =αQ/d ⁴(256)

[0172] Reducing the supply lumen radius to d/8 and increasing the returnlumen radius to 3d/8:

Δp _(s) =αQ/d ⁴(4096)

Δp _(r) =αQ/d ⁴(50.57)

And p _(b) =Δp _(r)=⅕ value for both diameters=d/4.

[0173] In other words, for the same catheter shaft size, the balloonpressure has been decreased by a factor of 5 with the identical flux.The above were assumed to be cylindrical side-by-side lumens, but otherlumen shapes would have similar results.

[0174] In these embodiments as well, it may be desirable to treat thesurface of the heat transfer element to avoid clot formation because theheat transfer element may dwell within the blood vessel for extendedperiods of time, such as 24-48 hours or even longer. One means by whichto prevent thrombus formation is to bind an antithrombogenic agent tothe surface of the heat transfer element. For example, heparin is knownto inhibit clot formation and is also known to be useful as abiocoating.

[0175] Referring back to FIG. 19, an embodiment of the method of theinvention will be described. A description with reference to the otherembodiments is analogous. A guide catheter or wire may be disposed up toor near the area to be cooled or heated. The heat transfer element maybe fed over the guide wire to the area. The movement of the heattransfer element is made significantly more convenient by theflexibility of the heat transfer element as has been described above.

[0176] Once the heat transfer element 272 is in place, a working fluidsuch as saline or other aqueous solution may be circulated through theheat transfer element 272 to inflate the same. Fluid flows from a supplycatheter into the inlet lumen 276. At the distal end 280 of the heattransfer element 272, the working fluid exits the inlet lumen 276 andenters the outlet lumen 274.

[0177] In the case of the embodiment of FIG. 22, the working fluid exitsthe inlet lumen and enters an outlet inflatable lumen 328 havingsegments 316, 318, 320, and 330. As the working fluid flows through theoutlet lumen 328, heat is transferred from the exterior surface of theheat transfer element 314 to the working fluid. The temperature of theexternal surface may reach very close to the temperature of the workingfluid because the heat transfer element 314 is constructed from verythin material.

[0178] The working fluids that may be employed in the device includewater, saline or other fluids that remain liquid at the temperaturesused. Other coolants, such as freon, undergo nucleated boiling and maycreate turbulence through a different mechanism. Saline is a safecoolant because it is non-toxic and leakage of saline does not result ina gas embolism that may occur with the use of boiling refrigerants.

[0179] By enhancing turbulence in the coolant, the coolant can bedelivered to the heat transfer element at a warmer temperature and stillachieve the necessary heat transfer rate. In particular, the enhancedheat transfer characteristics of the internal structure allow theworking fluid to be delivered to the heat transfer element at lower flowrates and lower pressures. This is advantageous because high pressuresmay stiffen the heat transfer element and cause the same to push againstthe wall of the vessel, thereby shielding part of the heat transfer unitfrom the blood. Such pressures are unlikely to damage the walls of thevessel because of the increased flexibility of the inflated device. Theincreased heat transfer characteristics allow the pressure of theworking fluid to be delivered at pressures as low as 5 atmospheres, 3atmospheres, 2 atmospheres or even less than 1 atmosphere.

[0180] In a preferred embodiment, the heat transfer element creates aturbulence intensity greater than 0.05 in order to create the desiredlevel of turbulence in the entire blood stream during the whole cardiaccycle. The turbulence intensity may be greater than 0.055, 0.06, 0.07 orup to 0.10 or 0.20 or even greater.

[0181] As shown in FIG. 25, in another embodiment of the invention. thecooling apparatus 368 of the present invention includes a flexiblemultilumen catheter 370, an inflatable balloon 372, and a plurality ofblood flow passageways 16 through the balloon 372. The balloon 372 isshown in an inflated state, in a selected position in a common carotidartery CC.

[0182] The balloon 372 is attached near a distal end of the flexiblecatheter 370. The catheter 370 can have at least a cooling fluid supplylumen 380 and a cooling fluid return lumen 382, with the cooling fluidsupply lumen 380 preferably being located substantially within thecooling fluid return lumen 382. The catheter 370 can also have aguidewire lumen 384, for the passage of a guidewire 386, as is known inthe art.

[0183] The balloon 372 can be formed from a flexible material, such as apolymer. The balloon 372 can be constructed to assume a substantiallycylindrical shape when inflated, with a proximal aspect 374 and a distalaspect 378. The balloon 372 can have a plurality of tubular shaped bloodflow passageways 376 formed therethrough, from the proximal aspect 374to the distal aspect 378. The tubular walls of the passageways 376constitute a heat transfer surface, for transferring heat from the bloodto the cooling fluid. The flexible material of the tubular passageways376 can be, at least in part, a metallized material, such as a filmcoated with a thin metal layer, either internally, externally, or both,to aid in heat transfer through the passageway walls. Alternatively, thetubular passageways 376 can be constructed of a metal-loaded polymerfilm. Further, the remainder of the balloon 372 can be coated with athin metallized layer, either internally, externally, or both, or ametal-loaded polymer film. The proximal aspect 374 and the distal aspect378 of the balloon can also constitute a heat transfer surface, fortransferring heat from the blood to the cooling fluid. The guidewirelumen 384 of the catheter 370 can also pass through the balloon 372,from the proximal aspect 374 to the distal aspect 378.

[0184] As shown in FIG. 26, each tubular passageway 376 has a proximalport 388 in a proximal face 390 on the proximal aspect 374 of theballoon 372, and a distal port 392 in a distal face 394 on the distalaspect 378 of the balloon 372. A cooling fluid supply port 396 near thedistal end of the cooling fluid supply lumen 380 supplies chilled salinesolution from a chiller (not shown) to the interior of the balloon 372,surrounding the blood flow passageways 376. A cooling fluid return port398 in the cooling fluid return lumen 382 returns the saline solutionfrom the interior of the balloon 372 to the chiller. Relative placementof the cooling fluid ports 396, 398 can be chosen to establish flowcounter to the direction of blood flow, if desired.

[0185]FIG. 27 shows the proximal aspect 402 of the balloon 372 and givesa view through the blood flow passageways 376, illustrating the generalarrangement of the blood flow passageways 376, cooling fluid supplylumen 380, cooling fluid return lumen 382, and guidewire lumen 384,within the outer wall 400 of the balloon 372.

[0186]FIG. 28 is a side elevation view of the apparatus 368, with apartial longitudinal section through the balloon wall 400, showing onepossible arrangement of the cooling fluid supply port 396 and thecooling fluid return port 398 within the balloon 372.

[0187] In practice, the balloon 372, in a deflated state, is passedthrough the vascular system of a patient on the distal end of thecatheter 370, over the guidewire 386. Placement of the guidewire 386 andthe balloon 372 can be monitored fluoroscopically, as is known in theart, by use of radiopaque markers (not shown) on the guidewire 386 andthe balloon 372. When the balloon 372 has been positioned at a desiredlocation in the feeding artery of a selected organ, such as in thecommon carotid artery feeding the brain, fluid such as saline solutionis supplied through the cooling fluid supply lumen 380. This fluidpasses through the cooling fluid supply port 396 into the interior ofthe balloon 372, surrounding the tubular passageways 376, to inflate theballoon 372. Although the balloon 372 can be formed to assume asubstantially cylindrical shape upon unconstrained inflation, theballoon 372 will essentially conform to the shape of the artery withinwhich it is inflated. As the balloon 372 inflates, the blood flowpassageways 376 open, substantially assuming the tubular shape shown.

[0188] When the balloon 372 has been properly inflated, blood continuesto flow through the feeding artery CC by flowing through the blood flowpassageways 376, as indicated, for example, by the arrows in FIG. 25.The size and number of the blood flow passageways 376 are designed toprovide a desired amount of heat transfer surface, while maintaining asuitable amount of blood flow through the feeding artery CC. Return flowto the chiller can be established, to allow flow of cooling fluidthrough the cooling fluid return port 398 and the cooling fluid returnlumen 382 to the chiller. This establishes a continuous flow of coolingfluid through the interior of the balloon 372, around the blood flowpassageways 376. The return flow is regulated to maintain the balloon372 in its inflated state, while circulation of cooling fluid takesplace. The saline solution is cooled in the chiller to maintain adesired cooling fluid temperature in the interior of the balloon 372, toimpart a desired temperature drop to the blood flowing through thetubular passageways 376. This cooled blood flows through the feedingartery to impart the desired amount of cooling to the selected organ.Then, cooling fluid can be evacuated or released from the balloon 372,through the catheter 370, to deflate the balloon 372, and the apparatus368 can be withdrawn from the vascular system of the patient.

[0189] Temperature Sensing

[0190] A guidewire may also be employed to assist in installing thedevice. The tip of the guidewire may contain or be part of a temperaturemonitor. The temperature monitor may be employed to measure thetemperature upstream or downstream of the heat transfer element andcatheter, depending on the direction of blood flow relative to thetemperature monitor. The temperature monitor may be, e.g., athermocouple or thermistor.

[0191] An embodiment of the invention may employ a thermocouple which ismounted on the end of the guidewire. For the temperatures considered inblood heating or cooling, most of the major thermocouple types may beused, including Types T, E, J, K, G, C, D, R, S, B.

[0192] In an alternative embodiment, a thermistor may be used which isattached to the end of the guidewire. Thermistors arethermally-sensitive resistors (or “RTD”s, resistance temperaturedevices) whose resistance changes with a change in body temperature. Theuse of thermistors may be particularly advantageous for use intemperature-monitoring of blood flow past cooling devices because oftheir sensitivity. For temperature monitoring of body fluids,thermistors that are mostly commonly used include those with a largenegative temperature coefficient of resistance (“NTC”). These shouldideally have a working temperature range inclusive of 25° C. to 40° C.Potential thermistors that may be employed include those with activeelements of polymers or ceramics. Ceramic thermistors may be mostpreferable as these may have the most reproducible temperaturemeasurements. Most thermistors of appropriate sizes are encapsulated inprotective materials such as glass. The size of the thermistor, forconvenient mounting to the guidewire and for convenient insertion in apatient's vasculature, may be about or less than 15 mils. Largerthermistors may be used where desired. Of course, various othertemperature-monitoring devices may also be used as dictated by the size,geometry, and temperature resolution desired.

[0193] A signal from the temperature-monitoring device may be fed backto the source of working fluid to control the temperature of the workingfluid emerging therefrom. In particular, a catheter may be connected toa source of working fluid. A proximal end of a supply lumen defined by asupply tube is connected at an output port to the source of workingfluid. The return lumen defined by a return tube is similarly connectedat an input port to the source of working fluid. The source of workingfluid can control the temperature of the working fluid emerging from theoutput port. A signal from a circuit may be inputted to the source ofworking fluid at an input. The signal from the circuit may be from thethermocouple, or may alternatively be from any other type oftemperature-monitoring device, such as, as noted above, at the tip ofthe guidewire.

[0194] The signal may advantageously be employed to alter thetemperature, if necessary, of the working fluid from the source. Forexample, if the temperature-monitoring device senses that thetemperature of the blood flowing in the vessel of the patient'svasculature is below optimal, a signal may be sent to the source ofworking fluid to increase the temperature of the working fluid emergingtherefrom. The opposite may be performed if the temperature-monitoringdevice senses that the temperature of the blood flowing in the feedingvessel of the patient's vasculature is above optimal.

[0195] Console

[0196] With reference to FIG. 29, an embodiment of a console system 544includes a heat transfer catheter 546, a control system 548, and acirculation set 550 housed by the control unit system 548. The controlsystem 548 may be equipped with an output display 552 and input keys 554to facilitate user interaction with the control system 548. A hood 556may be pivotally connected to a control unit housing 558 for coveringmuch of the circulation set 550.

[0197] Circulation Set

[0198] With reference to FIGS. 29 and 30, an embodiment of thecirculation set 550 will now be described. The circulation set 550include one or more of the following: a fluid reservoir 574, a pump 576,a filter 578, a heat exchanger 580, a temperature and pressure sensorassembly 584, a supply line 586, and a return line 588. A supply lumenport 570 and a return lumen port 572 are coupled to respective supplylines 586 and return lines 588 of the circulation set 550. The supplyline 586 and return line 588 are preferably comprised of one or morepieces of tubing, connectors, etc. for joining the aforementionedcomponents of the circulation set 550 to the supply lumen port 570 andreturn lumen port 572. The circulation set 550 may supply, filter,circulate, and/or be used to monitor the temperature and pressure of theheat transfer fluid for the catheter 546.

[0199] In some embodiments, there may not be a need to measure thepressure, but rather the same may be deduced by a calculation. Inparticular, pressure is a function of I, the current to the pump, ω/∂t,the pump speed, and Q, the mass flux from the pump. But Q=ζ*∂ω/∂t, whereζ is the efficiency of the pump. Thus, p=p(I, ω/∂t). Analogously to theelectrical case, where Power=IE or IV, here Power=pressure*mass flux orp*ζ*∂ω/∂t, or p=I*[E/(ζ*∂ω/ t)]. As E is a constant, pressure p may bedetermined by measuring I and ω/∂t. ζ may be determined in the lab andthen used in the field.

[0200] Temperature Monitoring

[0201] Closed loop control of thermal therapy such as that provided bythe system requires feedback of a temperature signal which representsthe state of the patient, human or animal, to which the therapy isapplied. This signal, combined with the target temperature of thetherapy, serves as an input to a PID type control algorithm whichregulates the energy added to or removed from the patient.

[0202] In such a system, the servo gain may be set to deliver maximumsystem power with approximately a 0.2 C. servo error. With a PIDcontroller, having zero coefficients for the integral and derivativeterms, the controller may provide a proportional linear drive signalfrom 0% power, with a servo error=0 C., to 100% power with a servo errorof 0.2 C. or more.

[0203] Choosing the correct physiologic site for acquisition of thisfeedback signal is important to the success of the therapy. Since thethermal modifications induced by the system are applied directly to thecore of the patient, the control signal should ideally represent thethermal state (temperature) of the core compartment. With currentclinically accepted temperature monitoring practice, core temperature isavailable through esophageal or naso-esophageal, tympanic, bladder, orrectal probes. While any of these may represent the temperature of apatient in equilibrium with the environment (i.e. one not subject torapid temperature change), certain locations, such as bladder and rectaltemperatures, described in more detail below, have been shown to lag theresponse of the core during intervals of rapid core temperature change.Additionally, esophageal, naso-esophageal, and tympanic probes may beacceptable for use in heavily sedated patients but are uncomfortable orotherwise impractical for use in lightly sedated or awake patients. Insome instances, monitoring temperature in the distal esophagus isappropriate for monitoring core body temperature of a patient and forproviding temperature feedback for controlling the induction andmaintenance of hypothermia. However, for some patients, including strokeand AMI patients, esophageal temperature monitoring is not practical asthese patients are often awake.

[0204] Other monitoring sites may be employed, including tympanic andbladder. However, even these monitoring sites are not ideal. Forexample, a tympanic temperature probe may cause patient discomfort andmay be pulled out during the monitoring period. If this happens, thesystem will turn off as the patient temperature is already beingmeasured as hypothermic at room temperature. The bladder temperatureprobe does not represent in real time the dynamic temperature changesthat are occurring in the core. There is a significant lag of time, suchas a 20 to 40 minute delay, and an effect of 1 to 2° C. that may makethe same not represent the true core temperature.

[0205] Thus, to induce and control hypothermia in an awake patientrequires a more reliable and accurate monitoring site that is not tooinvasive. A pulmonary artery (PA) temperature sensor located in aSwan-Ganz pulmonary artery catheter could be a reliable temperaturesite, but this requires another invasive catheter procedure, which isnot indicated for stroke patients. Alternatively, a central venouscatheter could measure the temperature of the blood entering the rightatrium, but again this may be too invasive.

[0206] A sensor mounted on the interior of the catheter would addressboth of these problems by eliminating the need for a separate invasivetemperature probe and ensuring accurate control temperature measurementdue to the central placement of the catheter in the IVC. Since thetemperature inside the catheter and its external environment maytypically differ by 10-40° C. during operation, due to the presence ofwarm or cold heat transfer fluid within the catheter, acquisition of anaccurate control temperature from a catheter mounted probe, such as athermistor, may involve temporary cessation of therapy by halting theflux of heat transfer fluid. After the flux of heat transfer fluid ishalted, a finite interval may elapse before thermal equilibration orrelaxation of the catheter with its environment. Interrupting therapyfor acquisition of the control temperature may tend to reduce theaccuracy of the controller. A predictive algorithm allows computation ofa useful control temperature which does not require waiting for completeequilibration and thus measurement of patient core temperature. Onemethod for prediction of the equilibrium temperature, based on anassumed functional form for the relaxation history, is presented below.

[0207] In one embodiment, as an initial calculation, by measuring thetemperature of the catheter working fluid returning to the console, onecan determine or estimate the power delivered or consumed by thecatheter's heat exchanger.

[0208] For example,

P _(delivered to catheter)=(T _(R) −T _(S))·(flow rate)·4.17 W−°C.-cc/sec

[0209] This power is directly affected by the patient's temperature.Less power is delivered with a warmer core temperature than a colderone. In general, the power delivered is proportional to the temperaturegradient between the patient's blood temperature and the temperature ofthe heat exchanger:

P_(delivered)(Watts)∝f(T_(patient), . . . )

[0210] Going from a patient temperature of 37° C. to 33° C. would lowerthe power approximately${1 - \frac{33 - {4{^\circ}\quad {C.}}}{37 - {4{^\circ}\quad {C.}}}} \cong {12.1\quad \%}$

[0211] Thus, by monitoring the decrease or increase in power applied orabsorbed by the catheter, one can estimate a useful control temperature,or at least the blood temperature, indirectly. By knowing the startingpatient temperature (e.g., the clinician could enter a valuecorresponding to the patient temperature via an IR ear thermometer) andprogramming in a desired patient temperature, the device couldcontrollably cool or heat the patient. By monitoring the returntemperature change, the instrument could control to the desiredhypothermic state.

[0212] Referring to FIG. 31, the console 750 may measure the temperatureof the catheter “coolant” or working fluid in both directions: i.e., thetemperature of the fluid 752 being supplied T_(S) to the catheter andthe temperature of the fluid 754 returning from the catheter T_(R). Thistemperature may be measured at the console 750 via, e.g., thermistorpins that interface with a disposable circulation set.

[0213] Another way to measure the latter temperature, e.g., the cathetercoolant return temperature, is to mount a temperature sensor 756 in thecatheter heat transfer element 758 in the return lumen 760 of thecatheter (see FIG. 32). This may yield a more precise measurement.

[0214]FIG. 33, described in more detail below, shows an alternateembodiment where a distal-tip-mounted temperature sensor is employed. Bymeasuring the coolant return temperature T_(R) in the catheter at theHTE, one can measure the instantaneous power absorbed or delivered tothe blood stream. This power may be proportional to the actual bloodtemperature. In the cooling mode, as the blood temperature decreases,the power delivered to the catheter decreases since the temperaturegradient is less. This is also true, in the converse sense, in therewarming mode. As the patient warms, less power is delivered to theblood stream. This relationship can be approximated by $\begin{matrix}{{\Delta \quad {power}\quad {absorbed}\text{/}{delivered}} \cong \frac{T_{{patient}_{1}} - T_{{bath}_{1}{return}}}{T_{{patient}_{2}} - T_{{bath}_{2}{return}}}} \\{{T_{{patient}_{N}} = {{patient}\quad {blood}\quad {temperature}\quad {near}\quad {catheter}}}{\quad \quad}{{heat}\quad {exchanger}\quad {at}\quad {time}\quad N}} \\{{{T_{{bath}_{N}}{return}} = {{Temperature}\quad {of}\quad {coolant}\quad {returning}}}\quad \quad {{to}\quad {the}\quad {heat}\quad {exchanger}\quad ({console})\quad {at}\quad {time}}} \\{{\quad \quad}{N\quad {or}\quad {as}\quad {measured}\quad {at}\quad {the}\quad {catheter}\quad {heat}\quad {exchanger}}\quad}\end{matrix}$

[0215] The console 750 can measure the instantaneous power that is beingdelivered or absorbed by the catheter 762, and by monitoring the changein power delivered as cooling or warming is being administered, one canpredict or estimate a new control temperature value if the originaltemperature is known. Therefore, the following relationship exists:

[0216] New control temperature estimate α

[0217] f(initial blood temperature, initial power, current power)

[0218] This relationship may have other sensitivities which alter “thechange in catheter power” to “change in blood temperature” relationship.For example, if the blood flow changes dramatically during this period,the catheter heat exchanger efficiency may change. Higher cardiacoutputs would allow for more power absorption or delivery.

[0219] To correct for this effect, the catheter coolant flow can bestopped and the HTE can come to equilibrium with the blood temperature.At this equilibrium, the temperature sensor on the HTE would bemeasuring the temperature of the blood. This measurement may be used tocorrect the estimate for future blood temperature predictions. Adetermination may then be performed as to how often it is necessary tostop the pump and recalibrate the algorithm that provides real timeblood temperature estimates.

[0220] where:

[0221] T_(S)=Temperature of the coolant entering catheter

[0222] T_(R)=Temperature of the coolant returning from the catheter

[0223] T_(B)=Temperature of the blood indirectly estimated by turningoff the flow of coolant in the catheter.

[0224] This method estimates the blood temperature between the “pumpoff” states and the run states.

[0225] Certain variables require a certain level of estimation. First,the pump needs to be “off” a set period of time to reach equilibriumwith the blood flowing around the HTE.

[0226] For example, it may take 60 seconds to 120 seconds for the HTEoutlet sensor to achieve a temperature equilibrium with the flowingblood.

[0227] In addition, an estimation algorithm can be employed to predictthe steady state temperature. For example, referring to FIG. 34, thetemperature measured by a catheter-mounted thermistor at a time of fullpump activity may be, e.g., 10 C., at time t=0. If at this time the pumpis turned off, the temperature as measured rises according to curve 766up to an equilibrium temperature. If at time t=1 the pump is turned backon, then the temperature cools again according to curve 768. A dutycycle may be defined by:${{duty}\quad {cycle}} = \frac{{pump}\quad {‘{on}’}\quad {time}}{{{pump}\quad {‘{on}’}\quad {time}} + {{pump}\quad {‘{off}’}\quad {time}}}$

[0228] A good duty cycle may be, e.g., >90%.

[0229] The duty cycle can be enhanced, i.e., >90%, if a predictivealgorithm is employed to shorten the time that the pump is off.Referring to FIG. 35, an algorithm that predicts the control temperatureallows the measurement of temperature to occur in a shortened span oftime, thus shortening the pump “off” time and raising the duty cycle.The following example demonstrates the principle that the patienttemperature can be altered, at least for a predetermined time, withoutconstantly monitoring the patient temperature.

[0230] The patient core temperature can move somewhat during periods ofmaximum drive by the system. For example, it has been seen that anaverage cooling rate may be 5° C./hr and an average warming rate may be2° C./hr. Assuming these values, in 10 minutes, the body temperature canchange

[0231] 0.8° C. cool down/10 minutes and

[0232] 0.3° C. warmup/10 minutes

[0233] After this initial interval, e.g., 10 minutes, the algorithm maysample more rapidly as it nears to the desired target value. Forinstance, if the patient initial temperature is 37° C. and the goal is33° C., a 4° C. change, the device can anticipate that a minimum of 30minutes to 45 minutes will be required to induce a 4° C. coretemperature change. Thus, the device can start cooling with maximumpower for 30 minutes, then stop the pump and check the temperature.

[0234] As the temperature nears the set point, sampling may be morefrequent. Table I shows a sample sampling algorithm that changes thefrequency of stopping the pump and measuring temperature as thetemperature difference between patient target temperature and projectedcontrol or projected or measured blood temperature is lowered. TablesIII and IV show more detailed analysis of the rates.

TEMPERATURE SENSOR LOCATED WITHIN THE HTE Example 1(Adjacent-Proximal-Bond-Mounted)

[0235] Referring back to FIG. 32, a thermocouple 756, such as a “T”type, was bonded into the proximal bond 764 of the catheter's HTE 762(e.g., a 14 fr. HTE). With the system running in the maximum coolingphase, the HTE sensor 756 was measuring a temperature of approximately18° C. Upon stopping the circulation pump, the sensor's temperature roseexponentially to 37.4° C., with a time constant of approximately 10 to12 seconds. The actual temperature read as a function of time is as perTable II.

[0236] As may be seen, stopping the pump for 30 seconds, the temperaturesensor approached to approximately 0.3° C. of the final temperature.Stopping the pump for 20 seconds, the sensor will be short about 0.7° C.of the final value.

Example 2 (Tip-Mounted)

[0237] Referring to FIG. 33, a catheter heat transfer tip assembly 800is shown having a catheter tube 802 and a heat transfer tip 804 that arebonded together at a proximal bond 806. The assembly 800 includes asupply lumen 808 and a return lumen 810. Fluid within supply lumen 808is in pressure communication with fluid within return lumen 810 via askive 812. The directions of fluid flow are indicated by the arrowswithin lumens 808 and 810, although of course these may be reversed ifdesired. A guidewire lumen 814 may be disposed adjacent the supply lumen808.

[0238] A thermocouple or thermistor assembly 816 may be disposed at oradjacent the distal tip of the heat transfer tip, such as by beingbonded to the exterior of the guidewire lumen 814. The assembly 816 mayinclude a thermistor or thermocouple 818, which may be encapsulated witha polymer sleeve 820 such as polyimide or polyethylene. Instead of oradditionally, an encapsulation with a UV curable loctite adhesive (notshown) may take place. Finally, for strength, the encapsulated sensormay be placed into a hypotube 822, which may be a small stainless steeltube.

[0239] Sensor wires 824 may communicate signals from the temperaturesensor to the control circuitry. As the wires are typically too large tofit in the return lumen 810, principally due to the bellows of the heattransfer tip, the same may traverse from the return lumen 810 (wherethey are disposed proximal of the proximal bond 806) to the supply lumen808 (where they are disposed distal of the proximal bond 806). Thistraversal may occur at an entry point 826, which is generally a hole.This arrangement has an additional benefit that the wires are out of thehigh pressure supply lumen for most of their length.

Example 3 (Sheath-Mounted)

[0240] In yet another embodiment, the temperature sensor may be mountedon the introducer sheath used for catheter installation. In this case,the temperature sensor would be disposed on a part of the sheath that iswithin the vascular system.

Example 4 (Balloon-Mounted)

[0241] In yet another embodiment, the temperature sensor may be mountedon a portion of the helical balloon embodiment disclosed above. Forexample, the same may be mounted on the exterior of the balloon at thedistal tip, to achieve a temperature reading most indicative of corebody temperature. However, for convenience, the temperature sensor mayalso be mounted at various other locations, either on or within theballoon. In any case, the sensor may have a polymer shield and/ormetallic shield discussed above. As in the other embodiments, flow maybe interrupted for a short period of time to allow the temperaturemeasured by the sensor to begin to relax to an equilibrium temperature,and from the temperatures measured during this relaxation a projectionto measure a control temperature may be made.

[0242] Predictive Algorithm

[0243] Determination of Time Constant

[0244] The time constant of the response is proportional to the trappedvolume of saline in the HTE. A 24 cm 14 fr. HTE will containapproximately the following amount of saline:

[0245] 14 fr.

Π r²×l saline volume

Π (0.23² cm²)×24 cm 4 cm³

[0246] A 24 cm 9 fr. HTE will contain approximately the following amountof saline: $\underset{\_}{9\quad {{fr}.}}$V = x  r² × l = (0.15²  cm²) × 24  cm = 1.7  cm³

[0247] Therefore, the time constant of a 9 fr. dual element HTE shouldbe$\frac{1.7}{4} = {{4.25\quad \% \quad {of}\quad {the}\quad 14\quad {{fr}.}} \approx {4\quad {to}\quad 5\quad {seconds}}}$

[0248] Thus, for a 9 fr. catheter, the “pump off” time can be reduced toapproximately 10 seconds to 15 seconds.

[0249] Example Procedure

[0250] 1. Input the desired “target temperature” and rate if desired.

[0251] 2. Estimate patient temperature from HTE sensor={circumflex over(T)}_(P) _((O)) pump “off” for e.g., 30 seconds.

[0252] 3. Device calculates “servo error”

{circumflex over (T)} _(patient) _((O)) −T _(Target) _((O)) =E(O).

[0253] 4. Device determines time interval to cool or warm, depending onsize of E(O) (see Table V).

[0254] 5. Stop pump at the end of the heating/cooling interval.

[0255] 6. Capture temperature data from HTE sensor at, e.g., 0.1 secondsampling rates

[0256] 9 fr capture 15 seconds of data

[0257] 14 fr. capture 30 seconds of data

[0258] 7. Estimate control temperature and display value. Input thisvalue to the temperature control servo loop.

[0259] 8. Start pump up depending on servo error (see Table VI):

where Servo Error={circumflex over (T)} _(patient(N)) −T _(T arget(O))

[0260] Alternatively, the pump power can be made proportional to theservo error.

[0261] An alternative method for determining the interval to drive thesystem before stopping the pump is as follows:

[0262] Assuming

[0263] T_(O)(t)=Starting patient temperature; and

[0264] T_(T)=Target temperature,

[0265] The maximum rate of cooling or heating${\frac{\left\lbrack {{T_{o}(t)} - \left( {T_{t} + {0.5{^\circ}}} \right)} \right\rbrack}{R_{\max}{\,\quad {^\circ}}\quad {C.\text{/}}\min}} = {{Time}\quad {minutes}}$

[0266] One approach to determining a projected control temperature is asfollows. Referring to FIG. 36, the exponential T(t) is shown. Area A1 isthe area under T(t) during the first 10 seconds and Area A2 is the areaunder T(t) during the next 10 seconds.

[0267] If the assumption is made that $\begin{matrix}{{{\frac{A1}{A2} = {\frac{{Area}\quad 1\quad {st}\quad 10\quad {Seconds}}{{Area}\quad 2\quad {st}\quad 10\quad {Seconds}} \propto B}},{{a\quad {time}\quad {constant}};}}\quad {{independent}\quad {of}\quad A}} \\{\frac{A1}{A2} = \left. \frac{\int_{0}^{10}{A\left( {1 - ^{\frac{- t}{B}}}\quad \right)}}{\int_{10}^{20}{A\left( {1 - ^{\frac{- t}{B}}}\quad \right)}}\Rightarrow\frac{{\int_{0}^{10}1} - {\int_{0}^{10}^{\frac{- t}{B}}}}{{\int_{0}^{20}1} - {\int_{0}^{20}^{\frac{- t}{B}}}} \right.} \\{\frac{A1}{A2} = {\frac{10 + {B\quad ^{\frac{- 10}{B}}} - {B\quad ^{\frac{- 0}{B}}}}{10 + {B\quad ^{\frac{- 20}{B}}} - {B\quad ^{\frac{- 10}{B}}}}\quad = {{Defining}\quad a\quad {unique}\quad {relationship}\quad {between}}}} \\{{{\frac{A1}{A2} = {f(B)}};{{for}\quad {every}\quad B}},{{there}\quad {is}\quad a\quad {well}\quad {defined}\quad {{A1}/{A2}}\quad {ratio}}} \\{\frac{A1}{A2} = \frac{10 + {B\quad ^{\frac{- 10}{B}}} - B}{10 + {B\quad ^{\frac{- 20}{B}}} - {B\quad ^{\frac{- 10}{B}}}}}\end{matrix}$

[0268] A1 and A2 can be measured numerically. From this, B can becalculated. Of course, a look-up table can be instituted for ease ofreference (see Table VII). Also see FIG. 37, in which each area A1 andA2 encompass 12 seconds sampling time.

[0269] Once B is determined from the look up table, A can be calculatedas follows: $\begin{matrix}{{{A1} + {A2}} = {A\left\lbrack {{\int_{0}^{10}\left( {1 - ^{\frac{- t}{B}}}\quad \right)} + {\int_{0}^{20}\left( {1 - ^{\frac{- t}{B}}}\quad \right)}} \right\rbrack}} \\{A = \frac{{A1} + {A2}}{20 + {B\quad ^{\quad \frac{- 20}{B}}} - B}}\end{matrix}$

[0270] The magnitude of correction can then be calculated.

T(t)=T _(B) +A(1−e ^(−t/B))

Temperature T(t) at end of A1+A2, t=20

T(20)=T _(B) +Â(1−e ^(−20/{circumflex over (B)}))

at

T(∞)=T _(B) +Â

or

T(∞)=T(20)+ΔT correction

ΔT correction=Âe^(−20/{circumflex over (B)})

@t=20

{circumflex over (T)}∞=T(20)+Âe ^(−20/{circumflex over (B)})

[0271] Estimated final value

[0272] Referring to FIG. 38, which changes the above to the case whereA1 and A2 encompassing non-equal time periods but equal areas:$\begin{matrix}\begin{matrix}{{A1} = {{\int_{0}^{12}{\left( {1 - ^{\frac{- t}{B}}}\quad \right){t}}} = {{\int_{0}^{12}{\quad t}} - {\int_{0}^{12}{^{\frac{- t}{B}}\quad {t}}}}}} \\{= {{12 + {B\quad ^{\quad \frac{- 12}{B}}} - B} = {12 + {12\quad ^{- 1}} - 12}}} \\{= {{12 - 0.367} = 4.4}}\end{matrix} \\{{{A1} = {4.4{^\circ}\quad {C.{- \sec}}}}\quad} \\{\begin{matrix}{{A2} = {{\int_{12}^{x}{\left( {1 - ^{\frac{- t}{B}}}\quad \right){t}}} = {{\int_{12}^{x}{\quad t}} - {\int_{12}^{x}{^{\frac{- t}{B}}\quad {t}}}}}} \\{= {\left( {x - 12} \right) + {B\quad ^{\quad \frac{- x}{B}}} - {B\quad e}}}\end{matrix}\quad} \\{{{A2} = {x - 12 + {B\left( {^{\frac{- x}{B}} - ^{\frac{- 12}{B}}} \right)}}}\quad}\end{matrix}$

[0273] Find x for which A1_(12 sec)=A2 $\begin{matrix}\begin{matrix}{{{{A1}/12}\quad \sec} = {{12 + {B\quad ^{\quad \frac{- 12}{B}}} - B} = {{{A2}/12} - x}}} \\{= {x - 12 + {B\quad ^{\quad \frac{- x}{B}}} - {B\quad ^{\quad \frac{- 12}{B}}}}}\end{matrix} \\{\quad {\left. \Rightarrow{24 + {2B\quad ^{\quad \frac{- 12}{B}}} - B} \right. = {x + {B\quad ^{\quad \frac{- x}{B}}}}}}\end{matrix}$

[0274] One can then solve x for certain B's, creating a look up tablewhich defines the range of possible time constants for a given catheter.

[0275] To implement the above, a device such as that schematically shownin FIG. 39 may be employed. In FIG. 39, sensor temperature T(t) ismeasured by switch 780 when the pump is shut off (stop 768). In FIG. 39,a sampling interval of 0.1 seconds is shown, but this can vary.

[0276] The calculation of A1/A2 proceeds next (step 770), followed bythe determination of B from the look-up table (step 772). A is thencalculated (step 774), and from this ΔT, i.e., the correction factor(step 776). The projected temperature T( ) may then be determined (step778). The various quantities discussed are shown in FIG. 40.

[0277] In more detail, and referring to FIG. 41, a state diagram isshown for an embodiment of the present invention. Steps according to thestate diagram include: turning the system power on (step 730) andperforming desired data entry. This data entry may include entering suchinformation as catheter size, target temperature, rate or period ofcooling or warming, and so on. Then the catheter and its accompanyingcirculation set may be connected to each other and to the console. Thesystem may then be purged (step 734). Following this, the system is inthe ‘stop’ mode (step 736), and the catheter may be inspected, inserted,etc. If desired, the system may enter a patient temperature mode in whatthe catheter-mounted thermistor may be employed to determine a controltemperature (step 738). In this case, a delay of some ‘X’ seconds iscaused to occur (step 740), followed by temperature measurement andaveraging (step 744) over Y seconds. Depending on catheter size, X canrange from zero seconds to, e.g., 24 seconds or more. Following X,during Y, various temperatures can be measured or otherwise determined,including T_(HTE)(t), T(t)_(CONTROL), and T(t)_(MONITOR). These may beacquired at, e.g., 10 Hz or such other frequency as may be desired. Theaverage trend, with respect to time, of the temperature of the patientmay be approximated by the average trend of the temperature of the HTE,i.e.,

T_(p)(t)≅T_(HTE)(t)

[0278] The patient temperature may then be displayed, e.g., for 2seconds (step 746). The run mode may then be entered (step 742), and thepatient cooled or warmed. The servo error may then be determined (step744). Once the size of the servo error is determined, the interval, overwhich it is safe to run in maximum cooling or heating mode, may then bedetermined (step 748). After this interval, the system pump is stoppedand a projection mode of the control temperature (step 782). The timethe system is stopped may be, e.g., 10 seconds to 45 seconds, such as 15seconds or 30 seconds. The projected temperature may then be the basisfor future calculations and, if desired, may be displayed.

[0279] As an example, during the induction phase of hypothermia, thepump is stopped approximately 3 to 5 times for about 15 to 30 secondseach, for each new patient temperature estimate. So the total cool downtimes are lengthened a few minutes over an average cool down time.

[0280]FIG. 42 shows a comparator switch which may be employed in anembodiment of the invention. In FIG. 86, the closing of switch 788initiates the integration of area A1 by integrator 784, and the closingof switch 790 initiates the integration of area A2 by integrator 786.

[0281] A different theoretical model is now employed to explain methodsof the embodiment of the present invention. To model the transientbehavior of the catheter immediately following the cessation of internalfluid flux, consider the simplified (axisymmetric) system of a circularcylinder with temperature T₀ immersed in a steady axial fluid flow withconstant temperature T_(c) far from the cylinder. If the temperature onthe interior of the cylinder varies with time but is uniform at eachlongitudinal section, then, assuming that the longitudinal variation oftemperature within the cylinder is small compared to the difference intemperature between the cylinder and its environment, the time rate ofchange of temperature at each section of the cylinder is given by$\begin{matrix}{\frac{\partial T}{\partial t} = {\alpha \left( {T_{C} - T} \right)}} & {{eq}.\quad 1}\end{matrix}$

[0282] where α is a constant which depends on the material properties ofboth the cylinder and the exterior fluid in addition to the kinematicsof the external flow field. This simplified analysis suggests that thetransient signal from a catheter-mounted temperature sensor willcorrelate with a function of the form

T(t)=T _(∞) −C exp(−αt)  eq. 2

[0283] where T_(∞) is the equilibrium temperature, C is the offset ofT_(∞) from the starting temperature (which is necessarily unknown in thecase of data with non-negligible noise), and α depends on the materialproperties of the catheter and heat transfer fluid in addition to thematerial properties and kinematics of the exterior environment. If therange of α can be empirically bounded, then a simple procedureconsisting of a sequence of 2-dimensional least squares fits to afunction with the form of eq.2 is sufficient to determine T_(∞) wheneveran updated control signal is required.

[0284] To determine T_(∞), fluid flux in the catheter is first halted.After a short period to allow dissipation of transient fluid motion,such as 15 seconds, a sequence of n temperature values T_(i) from anembedded thermistor are acquired at the rate 1/Δt, where Δt is the(constant) time interval between adjacent samples. For example, 30samples may be taken at 2 second intervals. In order to avoid thenon-linear system resulting from direct application of the method ofleast squares to the data T_(i) and a function with the form of eq.2, αis instead specified and the resulting 2-D linear system is solved.Assuming that in-vitro evaluation of catheter performance allows thestatement that:

α_(min)<α<α_(max)  eq. 3

[0285] for a specific catheter size, then the error between thetemperature data and a function with the form of eq.2 is defined forparticular α as $\begin{matrix}{{ɛ\left( \alpha_{j} \right)} = {\sum\limits_{i = 1}^{n}\quad \left( {T_{i} - \left( {T_{\infty,j} - {C_{j}{\exp \left( {{- \alpha_{j}}\quad t_{i}} \right)}}} \right)} \right)^{2}}} & {{eq}.\quad 4}\end{matrix}$

[0286] where α_(min)<α_(j)<α_(max). In practice, ε(α) is minimized withrespect to T_(∞) and C for a sequence of α_(j) over the domain specifiedin eq.3 with $\begin{matrix}{{\alpha_{j} = {{\left( {j - 1} \right)\frac{\left( {\alpha_{\max} - \alpha_{\min}} \right)}{m - 1}} + \alpha_{\min}}};{1 \leq j \leq m}} & {{eq}.\quad 5}\end{matrix}$

[0287] If the resulting discrete representation of the function{circumflex over (ε)}(α) (where {circumflex over (ε)} represents theminimum value of ε for a particular α) has a unique minimum in thedomain specified in eq.3, then the triplet (T_(∞),C,α) which producesthe best fit of the data T_(i) with the assumed functional form isdefined by the value of α associated with the minimum in {circumflexover (ε)}(α). The number of samples m is chosen to provide sufficientresolution of the resulting function {circumflex over (ε)}(α).

[0288] For each α_(j), the corresponding T_(∞,j) and C_(j) which resultin the minimum error {circumflex over (ε)}(α_(j)) are found by requiringthat the two partial derivatives $\begin{matrix}\begin{matrix}{\frac{\partial ɛ}{\partial T_{\infty}} = {- {\sum\limits_{i = 1}^{n}\quad {2\left( {T_{i} - \left( {T_{\infty} - {C\quad {\exp \left( {{- \alpha}\quad t_{i}} \right)}}} \right)} \right)}}}} \\{\frac{\partial ɛ}{\partial C} = {\sum\limits_{i = 1}^{n}\quad {2\left( {T_{i} - \left( {T_{\infty} - {C\quad {\exp \left( {{- \alpha}\quad t_{i}} \right)}}} \right)} \right){\exp \left( {{- \alpha}\quad t_{i}} \right)}}}}\end{matrix} & {{eq}.\quad 6}\end{matrix}$

[0289] must vanish. Expressing eq.6 in matrix form, $\begin{matrix}{{\begin{bmatrix}a_{11} & a_{12} \\a_{21} & a_{22}\end{bmatrix}\begin{bmatrix}T_{\infty} \\C\end{bmatrix}} = \begin{bmatrix}{RHS}_{1} \\{RHS}_{2}\end{bmatrix}} & {{eq}.\quad 7}\end{matrix}$

[0290] where $\begin{matrix}\begin{matrix}{a_{11} = {\sum\limits_{i = 1}^{n}(1)}} & {a_{12} = {- {\sum\limits_{i = 1}^{n}{\exp \left( {{- \alpha}\quad t_{i}} \right)}}}} \\{a_{21} = {\sum\limits_{i = 1}^{n}{\exp \left( {{- \alpha}\quad t_{i}} \right)}}} & {a_{22} = {- {\sum\limits_{i = 1}^{n}{\exp \left( {{- 2}\quad \alpha \quad t_{i}} \right)}}}}\end{matrix} & {{eq}.\quad 8}\end{matrix}$

[0291] and $\begin{matrix}\begin{matrix}{{RHS}_{1} = {\sum\limits_{i = 1}^{n}T_{i}}} \\{{RHS}_{2} = {\sum\limits_{i = 1}^{n}{T_{i}{\exp \left( {{- \alpha}\quad t_{i}} \right)}}}}\end{matrix} & {{eq}.\quad 9}\end{matrix}$

[0292] Solving for T_(∞) and C, we find $\begin{matrix}\begin{matrix}{T_{\infty} = \frac{{{RHS}_{1}a_{22}} - {{RHS}_{2}a_{12}}}{{a_{11}a_{22}} - {a_{21}a_{12}}}} \\{C = \frac{{{RHS}_{2}a_{11}} - {{RHS}_{1}a_{21}}}{{a_{11}a_{22}} - {a_{21}a_{12}}}}\end{matrix} & {{eq}.\quad 10}\end{matrix}$

[0293] Once T_(∞) and C are known, {circumflex over (ε)}(α_(j)) iscomputed with eq.4. Finally, α (and the corresponding T_(∞) and C) whichproduces the smallest least-squares error between the temperature dataand a function with the form of eq.2 is defined by the minimum of thediscrete representation of the function {circumflex over (ε)}(α).

[0294] If the function {circumflex over (ε)}(α) has no unique minimum,or if the minimum in {circumflex over (ε)}(α) is greater than aspecified limit, the results of the procedure outlined above are ignoredand the equilibrium temperature T_(∞) may be found by allowing thetemperature of the embedded temperature sensor to equilibrate with itsexternal environment.

[0295] Failure of the system identification algorithm may indicateimproper placement of the catheter (e.g., if the optimal is smaller than_(min), the catheter may not have adequate external blood flux,indicating placement in a branching vein instead of the IVC).

[0296] Alternately, if cannot reasonably be assumed constant over theduration of each therapy, then each instance of control signalacquisition, including the first instance following submission of the“run” command, must be treated as a system identification in which isdetermined in addition to T_(∞) and C. Then is assumed to be bounded asin the above. Then, with a specified interval , T_(∞) and C are computedto minimize, in the least squares sense, $\begin{matrix}{{ɛ_{j}\left( \alpha_{j} \right)} = {\sum\limits_{i = 1}^{n}\quad \left( {T_{i} - \left( {T_{\infty \quad j} - {C_{j}{\exp \left( {{- \alpha_{j}}t_{i}} \right)}}} \right)} \right)^{2}}} & {{eq}.\quad 11}\end{matrix}$

[0297] for each _(j) in the domain. ( ) then defines a function which,if the limits were chosen correctly, obtains a minimum within thedomain. This minimum in turn defines the time constant and subsequentlyT_(∞) and C corresponding to the best fit, in the least squares sense,function of the form represented with the samples of temperaturerelaxation data. The minimum of ( ) may be obtained by a simple sortingalgorithm if the function is computed with a relatively smallAlternatively, for a more sparse sampling of the function ( ), aquadratic form may be assumed and the minimum found analytically. Thisalternative approach may execute faster due to the relative cost of thequadratic curve fit as opposed to additional evaluations of equation 11.

[0298] Addition of 1^(st) Order Linear Term:

[0299] The basic exponential model outlined above is based on theassumption that the temperature of the external environment (i.e. bloodin the IVC) is constant over the interval during which the embeddedthermistor is allowed to equilibrate with that environment. In general,the temperature of the external environment may be not constant overthis interval.

[0300] While the catheter is in operation (e.g. in the cooling mode),the various compartments of the body, distinguished on the basis ofblood flux per unit mass, or specific blood flux, are in a dynamic statein which the heat removed by the catheter comes preferentially fromthose tissues for which the specific blood flux is greatest. Whencoolant flux in the catheter is halted, these physiologic compartmentswill tend to equilibrate. Tissues with the highest specific blood fluxwill warm relative to those with lower specific flux as internal bodyheat is redistributed. As the redistribution of heat occurs primarilythrough convective transport by blood, the temperature of theenvironment of the catheter must change as the physiologic compartmentsapproach equilibrium.

[0301] While the blood temperature in the vicinity of the cathetergenerally varies over the interval during which the catheterequilibrates with its environment, the functional form of that variationis not known. For simplicity, any time scale inherent in physiologictemperature variation may be assumed to be greater than the time scaleassociated with relaxation of temperature within the catheter and thusthe physiologic temperature variation may be described with a Taylorseries, $\begin{matrix}{{T_{ext}(t)} = \left. {{T_{ext}\left( {t = 0} \right)} + \frac{\partial T_{ext}}{\partial t}} \middle| {}_{t = 0}{{{\cdot \Delta}\quad t} + {O\left( {\Delta \quad t^{2}} \right)}} \right.} & {{eq}.\quad 12}\end{matrix}$

[0302] where T_(ext) is the temperature of the environment and t=0defines the instant when heat flux through the catheter is halted. Withthe above assumption, Δt, which is the time during which temperaturedata is acquired from the embedded thermistor, is ‘small’ relative tothe time over which significant physiologic temperature changes willoccur. In this situation, the variation of external temperature isaccurately modeled by a simple linear function. With this understanding,it is not unreasonable to append the functional form of eq.2 with alinear component to model the changing temperature of the externalenvironment

T(t)=T _(∞) −C exp(−αt)+βt  eq.13

[0303] where β is the unknown rate of change of external temperaturewhich occurs in the body after cessation of heat transfer through thecatheter.

[0304] The process for computation of the best fit function with theform of eq.13 to the temperature data acquired from the embeddedthermistor is analogous to that described for the simpler 3-dimensionalmodel. A series of values are assumed for α, and the resulting linearleast squares problem for the error between the empirical data and theassumed functional form are solved for the triplet (T_(∞), C, β). Thesolution is defined as the value of α and the associated (T_(∞), C, β)for which the least squares error is minimum.

[0305] Alternatively, one may assume another form for T_(ext)(t):

T _(ext)(t)=T _(ext) ^(∞)−(T _(ext) ^(∞) −T _(ext) ⁰)exp(−βt)  eq.14

[0306] in which T_(ext), T_(ext) ^(∞) and T_(ext) ⁰ are, respectively,blood temperature in the environment of the catheter, the relaxedtemperature of the blood in the environment of the catheter and thecorresponding temperature at cessation of catheter flux. The constant βis the characteristic relaxation rate of blood temperature. Substitutingblood temperature given in equation 14 for T_(c) in equation 1,$\begin{matrix}{\frac{T}{t} = {\alpha \left\{ {T_{ext}^{\infty} - {\left( {T_{ext}^{\infty} - T_{ext}^{0}} \right){\exp \left( {{- \beta}\quad t} \right)}} - T} \right\}}} & {{eq}.\quad 15}\end{matrix}$

[0307] The temperature measured by the sensor embedded in the catheteris then given by $\begin{matrix}\begin{matrix}{{T(t)} = {T_{ext}^{\infty} - {\frac{\alpha}{\alpha - \beta}\left( {T_{ext}^{\infty} - T_{ext}^{0}} \right){\exp \left( {{- \beta}\quad t} \right)}} +}} \\{{\left\{ {T_{0} - T_{ext}^{\infty} + {\frac{\alpha}{\alpha - \beta}\left( {T_{ext}^{\infty} - T_{ext}^{0}} \right)}} \right\} {\exp \left( {\alpha \quad t} \right)}}}\end{matrix} & {{eq}.\quad 16}\end{matrix}$

[0308] for α≠β. T₀ is the starting temperature in the catheter. Therequirement that α≠β is not overly restrictive in practice since thecharacteristic relaxation rate of the catheter is generally much largerthan the corresponding physiologic rate.

[0309] Correlation of equation 16 with a sequence of discretetemperature data samples requires the solution of a 5-dimensionalnon-linear least squares problem. The solution set (T₀,T_(ext)^(∞),T_(ext) ⁰,α,β) is obtained by assuming

α_(min)<α<α_(max)

β_(min)<β<β_(max)  eq.17

[0310] and solving for the remaining constants (T₀,T_(ext) ^(∞),T_(ext)⁰) via a sequence of (n×m) 3-dimensional linear least squares proceduressimilar to that described above, where n and m are, respectively, thenumber of discrete α and β values in the domains described by equation17. The best fit function with the form of equation 15 is chosen bysearching the resulting set of (n×m) 3-dimensional linear least squaressolutions for the combination of α and β which result in the smallestfit error.

[0311] In practice, insufficient computational resources are oftenavailable for real-time correlation of the functional form given inequation 14 with patient temperature data. Instead, predictions are madeusing the simpler 3-dimensional technique described above, and the moreinvolved 5-dimensional solution is employed for analysis of recordeddata. Comparison of solutions obtained through the 3 and 5-dimensionalcurve fitting procedures suggests that α is roughly 25% greater thanthat computed with the 3-dimensional procedure. This is not unexpectedsince variation of external temperature during catheter relaxation maybe included in the computation of α with the simpler 3-dimensionalprocedure.

[0312] 4 Application to AMI Patient Temperature Data:

[0313] Although the preferred result of the correlations described insections 2 and 3 is the computation of core body temperature,application of the algorithm also produces the characteristic relaxationrate α exhibited by the catheter temperature data during equilibrationwith the environment. This rate is useful for determining the degree towhich catheter temperature has relaxed during a finite acquisitioncycle. Expressing equation 2 in the form $\begin{matrix}{{\ln \left( \frac{\Delta \quad {T(t)}}{\Delta \quad T_{0}} \right)} = {{- \alpha}\quad t}} & {{eq}.\quad 18}\end{matrix}$

[0314] where

ΔT(t)=T(t)−T _(∞)

ΔT ₀ =T ₀ −T _(∞)  eq.19

[0315] the ratio of temperature differences can be seen to be correlatedwith the degree of relaxation exhibited by the catheter temperature datain a certain time interval. In practice, temperature at the site of theembedded sensor during operation is roughly 10 C., so that relaxation tobody temperatures of the order of 35 C. results in an initial offsetfrom equilibrium of ˜25 C. Requiring the catheter temperature to relaxto within 0.5 C. of the equilibrium value in order for cathetertemperature to accurately reflect body temperature, it is seen that

αt=3.91  eq.20

[0316] The minimum value α must attain in order to satisfy therequirement that catheter temperature is relaxed to within 0.5 C. in aspecified amount of time may now be determined. When t=90 sec.,α_(min.)=0.043.

[0317] In another example, for a less than 1% variation, then αt=4.6time constants. And for α=0.06, then about half the data falls into therange, i.e., passes successfully through the projection “window”. In anycase, a larger number of samples assists the issue of averaging.

Higher Order Variations of Physiologic Temperature

[0318] It should be clear to practitioners skilled in the art, given theteaching above, that the method described above for the assumedfunctional forms may be extended to a variety of additional forms withboth linear and non-linear improvements to the basic exponential model.

[0319] Flux Drift As Spatial Integrator

[0320] As before, the working fluid flux would be halted during the timethat a control temperature is obtained. With the heat transfer fluidflux halted, the heat path to the temperature sensor in eitherconfiguration is only conductive, through the plastic catheter shaft andthe static heat transfer fluid. The heat flux which causes thetemperature sensor to relax to the temperature of its environmenttherefore necessarily originates preferentially in the immediatevicinity of the temperature sensor. If, in some configurations, heatflux into the catheter is reduced in this vicinity, the necessaryrelaxation time increases and prediction or measurement of thetemperature will require longer sampling intervals. Such a configurationmay obtain when an introducer covers the temperature sensor, and in thiscase an additional thermal resistance would be imposed between thetemperature sensor and the environment.

[0321] To obviate this difficulty, instead of halting the heat transferfluid (working fluid) flux during temperature acquisition, the flux maybe reduced to a creeping flow so that heat conducted through the entiremetallic shell of the heat transfer tip is convected past thetemperature sensor. If the flux is sufficiently slow, fluid entering theheat transfer tip will equilibrate with blood temperature before passingthe temperature sensor. In this way, the entire metallic shell of theheat transfer tip is employed as a spatial integrator to minimize thedependence of the temperature sensor relaxation rate or temperature onthe properties of the immediate environment of the temperature sensor.

[0322] Other Considerations for Catheter-Mounted Temperature Sensors

[0323] Analysis of human clinical data has revealed the presence of (atleast) two distinct time scales associated with the relaxation ofcatheter temperature in the above system. One of these intrinsic timescales is related to the geometry of the catheter and the properties ofits environment (e.g., vessel diameter and blood flux) while the othertime scale appears to reflect a physiologically imposed time related toequilibration of (body) thermal compartments after cessation ofendovascular heat transfer. Both time scales appear to be related tosimple exponential decay of the associated physical process (i.e., heatflux into the catheter, and heat transfer between body compartments),and the temperature history recorded by the embedded temperature sensormay be a convolution of the two processes. Ideally, the resultingtemperature history appears as a rapid decay to within approximately 1°C. of the final value, governed by the catheter-intrinsic time scale,followed by a more gradual relaxation governed by the physiologic timescale. If the two time scales are distinct, a local asymptotictemperature related to the catheter-intrinsic time scale can beextrapolated through a simple non-linear least squares fit to a finitesample of catheter temperature data. This results in an approximation ofthe temperature which would have been obtained in the catheterenvironment in the absence of the 2nd process, i.e. equilibration ofbody compartments, which tends to occurs on a much longer time scale. Ifthe two time scales are similar, as might result if the thermal mass ofthe catheter were much larger, or if the sensor were located in a regionof restricted blood flux, then de-convolution of the two time scalesbecomes difficult and extrapolation of a useful asymptotic temperaturesomewhat more problematic.

[0324] Far distal placement of the temperature sensor, relative to andapart from the heat exchanger, may be associated with certaindisadvantages. Cold fluid inside the heat transfer element willinfluence the temperature recorded by a distally located sensor byextracting heat from the external blood before it passes over thesensor. If the thermal mass of the heat transfer element is large as,for example, in the case of a large diameter balloon, then the catheterintrinsic time scale will increase and prediction of the asymptotictemperature becomes difficult. In addition, turbulence or mixing in theblood may result in fluctuations in the recorded temperature if thesensor is close to the heat transfer element. However, moving the sensoreven further downstream may result in undesirable proximity of thesensor to tissue, such as cardiac tissue.

[0325] Placement of the temperature sensor within the catheter shaft(housing the heat transfer fluid supply and return lumens) may bedesirable. However, this necessitates careful consideration of thedynamics of fluid motion in the supply and return lumens. If thesupply/return lumens are symmetric, or the same size and/or shape, thenintroduction of the temperature sensor assembly into one of the lumenswill increase the associated pressure drop along that path. If thesensor is placed in the return lumen, pressure in the balloon willincrease, resulting in a mechanically stiffer balloon. If the sensor isplaced in the supply lumen, the flux of heat transfer fluid willdecrease unless pump pressure is increased. If instead the supply andreturn lumens are asymmetric, placement of the sensor assembly in thelarger return lumen may result in a negligible effect on catheterpressure and flux.

[0326] Use of a YSI-400 thermistor as the temperature sensing device maybe desirable. This may render the device compatible with most of thedigital thermometers in the clinical environment. If fluid pathrestrictions, as described above, necessitate the use of a smallerthermocouple device, the associated electronics (i.e. accurate andexpensive millivolt amplifiers with temperature compensated junctions)become more complicated and incompatible with the popular clinicalequipment. Additionally, thermocouple accuracy is generally less thanthat available with a thermistor.

Temperature Estimation Errors & Accuracy

[0327] The ability of the system to control to a desired set point ortarget temperature may be limited by the cooling power, degree ofthermal disturbance (discussed below), accuracy of measuring thetemperature within the catheter, patient temperature drift during thesampling period when the pump is turned off, and the accuracy of theestimation algorithm.

[0328] Clinical experience in neurosurgical settings has shown that thecooling power required to maintain hypothermia at 33° C. is less thanabout 20% of the maximum power capability of the system even when aconvective warming blanket is used during the hypothermia maintenanceperiod. With a servo gain of 0.2 C. for 100% power, a 20% load wouldyield a servo Type 1 offset of 20%×0.2 C.=0.04 C. error. For a 9 frcatheter which has about 65% of the 14 fr capability, this would yield aoffset error during hypothermia maintenance of approximately 30%×0.2C.=0.06 C. In the setting of stroke and acute myocardial infarction, thesteady state load during maintenance is approximately the same; i.e.,about 0.06 C. offset due to the need to continue to extract heat out ofthe patient to balance the patient's retained metabolic heat due tosurface warming.

[0329] The accuracy of the thermistor may have, e.g., a specification of+/−0.1 C. for 100% confidence (4 standard deviations) in the temperaturerange of 32 to 42 C. The electronics and signal processing may have,e.g., a specification of +/−0.1 C. (95% confidence=+/−2 S.D.) to coverthe initial calibration, dynamic temperature range, drift, and agingconsiderations. The calibration of the hardware temperature channels maybe checked and recalibrated if needed on, e.g., an annual basis. Theaccuracy of the thermistor and the hardware signal conditioning andprocessing is comparable to other commercially available temperaturemonitoring disposable sensors and equipment used routinely in thehospital operating room and intensive care settings for monitoringpatient temperature.

[0330] During the sample period of acquiring temperature sensor data,approximately 30 seconds for the 9fr and 60 seconds for 14fr device, thepatient can rewarm due to retained metabolic heat and cessation of heatextraction. In one clinical study, the maximum rate of rewarmingobserved was less than about 1.5 C./hour or approximately 0.025 C. in 60seconds.

[0331] A last error source is the ability of the temperature estimationalgorithm to predict the final value of the sensor's temperatureresponse to a step input. An error sensitivity analysis was conducted byvarying the sampling time duration (acquisition period) and comparingthe estimated temperature to the actual temperature. For 20 seconds ofsample points (total of 24 seconds of the pump being in the “off” mode),the standard deviation of the error was 0.1 C. Decreasing the samplepoints to 15 (total 19 seconds of pump off) increases the standarddeviation of error to 0.18 C. while increasing the sample points to 25(total of 29 seconds) decreases the standard deviation to 0.7 C. A 20sample point algorithm has been chosen for an optimal trade off of timeversus estimation accuracy.

[0332] Thus the temperature measurement and estimation accuracy hasvarious components, which can be considered statistically independenterror sources (See Table VIII). Summing these error sources would yieldthe maximum expected error, 95% confidence, of, e.g., about 0.51 C.Taking the root mean square error, i.e., RMS error, would be about 0.26C.

Potential Thermal Disturbances

[0333] One design goal of a closed loop servo controller is to havesufficient capability to maintain control during various loadconditions. This capability in embodiments of the present invention isexpressed as the maximum thermal power available to null out adisturbance, at what amount of energy is it delivered for a particularservo error magnitude, defined as the servo gain, and the responsivenessof the controller that may have intentional lags or leads in thefeedback controller for control stability. Since the patient's responseto a thermal input is typically slow, over hours, no additionalmagnitude or phase compensation may be required in the controller tooptimize stability. The key ingredient to loop stability is the servogain level, which has been chosen to be in the range of 500 to 800 wattsper degree C. of error depending on which catheter size is chosen. Withthis servo gain level, clinical studies have demonstrated few or noinstability problems with minimal steady state servo error and goodresponse.

[0334] A potential thermal disturbance would be an IV infusion of roomtemperature (cold) fluids. For a constant infusion rate of 1.4 ml/min (2liters per 24 hours) of 20 C. fluid, this would represent a thermalinput rate of about 2 watts. The system would have to develop a servoerror of approximately (2 watts)/(600 watts/C.) or 0.003 C. to correctfor this steady state thermal disturbance. Since 2 watts is well withinthe capability of embodiments of the present invention, this disturbancewould be well controlled.

[0335] A more challenging thermal disturbance would be a rapid bolusinfusion of fluids, such as 250 ml, in, e.g., 5 minutes. If the fluidwere not heated to body temperature, this would represent an infusionrate of about 1 cc/sec at 20 C. for an equivalent energy input of about70 watts for 5 minutes. It takes about 70 to 85 watts for one hour tolower the body temperature of an average patient, 70 kg weight, onedegree C. Thus, a 5 minute bolus would have the effect of lowering thetemperature {fraction (5/60)}th of one degree, 0.083 C., again wellwithin the capabilities of the present system to control.

[0336] In actual clinical deployment of embodiments of the presentinvention, a convective or electrical heating blanket may be used forpatient comfort and for depressing shivering. The blanket temperaturesetting and how much of the patient's body is exposed to the blanketwill determine the net transfer of energy from the patient to the room.Sessler et.al. estimate that a typical blanket can prevent 20 to 50watts of heat loss to the environment. A 50 watt heat preservation wouldrequire the embodied system to extract an additional 50 watts of coolingto maintain the thermal balance. The servo error would move to 50Watts/600 watts/C.=0.083 C., again well within the capability of thesystem.

[0337] In summary, most if not all of the thermal disturbances asdescribed above are within the capability of embodiments of the closedloop control system to maintain the target temperature within 0.5 C.

[0338] As previously mentioned, control algorithms are sometimes used tocontrol the rate at which heat is extracted from the body by thecatheter. These algorithms may be embodied in hardware, software, or acombination of both. The gain factor employed by such algorithms isdependent on the effective thermal mass of the body or organ beingcooled. Thus, it is important to determine the effective thermal mass sothat an appropriate gain factor can be calculated for the feedbackcontrol algorithm.

[0339] The mass of the body (organ or whole body) being cooled can beestimated by relating the power removed by the catheter to the powerlost by the body.

[0340] The power removed by the catheter may be expressed as follows:

P_(catheter)=Mc_(f)ΔT  (1)

[0341] Where M is the mass flow rate of the fluid circulating throughthe catheter (typically measured in terms of cc/s), c_(f) is the heatcapacity of the fluid, and ΔT is the temperature difference between theworking fluid as it enters the catheter and as it exits the catheter.Accordingly, P_(catheter) can be readily calculated by measuring themass flow of the circulating fluid and the temperature differencebetween the working fluid as it enters and exits the catheter.

[0342] The power removed by the catheter as determined by equation (1)may be equated to the power that is lost by the patient's body:

P _(catheter) =mc _(b) ∂T/∂t  (2)

[0343] Where P_(catheter) is now the power lost by the patient's bodyand has the value calculated by equation (1), m is the effective thermalmass of the body being cooled, c_(b) is the heat capacity of the body,and ∂T/∂t is the change in temperature per unit time of the mass beingcooled.

[0344] Accordingly, the effective thermal mass of the body being cooledis:

m=P _(catheter)/(c _(b) ∂T/∂t)  (3)

[0345] Since all the variables in equation (3) are either known or aremeasurable, the effective mass can be determined.

[0346] The mass calculated in this manner is an effective thermal massthat represents the portion of the body from which power is removed(i.e., the portion of the body that is cooled). The temperature changein equation (3) represents the temperature change of the portion of thebody being cooled. For example, if whole body cooling is to beperformed, the change of the core body temperature may be measured tocalculate mass in accordance with equation (3). In general, for wholebody cooling, if the patient is vasoconstricted, the effective mass mayrepresent about 50% of the total body mass. If the patient isvasodilated, the effective mass will be closer to the total body mass.

[0347] Alternatively, if only a selected organ such as the brain is tobe cooled, then the temperature change that will be used in equation (3)would be the temperature change of the organ, assuming of course thatthe organ can be at least briefly considered to be largely thermallyisolated from the remainder of the body. In this case the effective massthat is determined would be comparable to the mass of the organ. If theselected organ to be cooled is the brain, for example, the catheter isplaced in the common carotid artery, the internal carotid artery, orboth. The temperature changed used in equation (3) will be measured byinserting a temperature sensor into the brain or via a tympanic membranesensor, both of which are commercially available.

EXAMPLE

[0348] In an animal study, whole body cooling was accomplished byinserting the catheter through the femoral vein and then through theinferior vena cava as far as the right atrium and the superior venacava. Cooling was initiated by circulating a working fluid at a flowrate of 5 cc/sec. The temperature differential between the fluidentering the catheter and the fluid exiting the catheter was 17° C.Accordingly, the power extracted by the catheter was 354 watts.

[0349] The body core temperature was measured through the esophagus.Twenty minutes after cooling was initiated, the rate at which the coretemperature changed was measured over a period of about ten minutes,resulting in an average temperature change of about 4° C./hr.

[0350] From equation (3) above, the effective thermal mass is:

m=354 watts/(0.965 watts/kg·C.°)(10° c./hr)=37 kg

[0351] The total mass of the animal was 53 kg, and thus the effectivemass was found to be 69% of the total mass.

[0352] One practice of the present invention is illustrated in thefollowing non-limiting example.

Exemplary Procedure

[0353] 1. The patient is initially assessed, resuscitated, andstabilized.

[0354] 2. The procedure may be carried out in an angiography suite orsurgical suite equipped with fluoroscopy.

[0355] 3. An ultrasound or angiogram of the external jugular/superiorvena cava or femoral vein/inferior vena cava can be used to determinethe vessel diameter and the blood flow; a catheter with an appropriatelysized heat transfer element can be selected.

[0356] 5. After assessment of the veins, the patient is sterilelyprepped and infiltrated with lidocaine at a region where the femoralartery may be accessed.

[0357] 6. The, e.g., femoral vein is cannulated and a guide wire may beinserted to the inferior vena cava. Placement of the guide wire isconfirmed with fluoroscopy.

[0358] 7. An angiographic catheter can be fed over the wire and contrastmedia injected into the vein to further to assess the anatomy ifdesired.

[0359] 8. Alternatively, the femoral vein is cannulated and a 10-12.5french (f) introducer sheath is placed.

[0360] 9. A guide catheter may be placed into the inferior vena cava. Ifa guide catheter is placed, it can be used to deliver contrast mediadirectly to further assess anatomy.

[0361] 10. The cooling catheter is placed into the inferior vena cavavia the guiding catheter or over the guidewire.

[0362] 11. Placement is confirmed if desired with fluoroscopy.

[0363] 12. Alternatively, the cooling catheter shaft has sufficientpushability and torqueability to be placed in the inferior vena cavawithout the aid of a guide wire or guide catheter.

[0364] 13. The cooling catheter is connected to a pump circuit alsofilled with saline and free from air bubbles. The pump circuit has aheat exchange section that is immersed into a water bath and tubing thatis connected to a peristaltic pump. The water bath is chilled toapproximately 0° C.

[0365] 14. Cooling is initiated by starting the pump mechanism. Thesaline within the cooling catheter is circulated at 5 cc/sec. The salinetravels through the heat exchanger in the chilled water bath and iscooled to approximately 1° C.

[0366] 15. The saline subsequently enters the cooling catheter where itis delivered to the heat transfer element. The saline is warmed toapproximately 5-7° C. as it travels along the inner lumen of thecatheter shaft to the end of the heat transfer element.

[0367] 16. The saline then flows back through the heat transfer elementin contact with the inner metallic surface. The saline is further warmedin the heat transfer element to 12-15° C., and in the process, heat isabsorbed from the blood, cooling the blood to 30° C. to 35° C. Duringthis time, the patient may be warmed with an external heat source suchas a heating blanket. At any point in the procedure, thermoregulatorydrugs, such as anti-shivering drugs, may be administered.

[0368] 17. The chilled blood then goes on to chill the body. It isestimated that less than an hour will be required to cool the brain to30° C. to 35° C.

[0369] 18. The warmed saline travels back the outer lumen of thecatheter shaft and is returned to the chilled water bath where the sameis cooled to 1° C.

[0370] 19. The pressure drops along the length of the circuit areestimated to be between 1 and 10 atmospheres.

[0371] 20. The cooling can be adjusted by increasing or decreasing theflow rate of the saline. Monitoring of the temperature drop of thesaline along the heat transfer element will allow the flow to beadjusted to maintain the desired cooling effect.

[0372] 21. The catheter is left in place to provide cooling for, e.g.,6-48 hours.

[0373] It is envisioned that the following veins may be appropriate topercutaneously insert the heat transfer element: femoral, internaljugular, subclavian, and other veins of similar size and position. It isalso envisioned that the following veins may be appropriate in which todispose the heat transfer element during use: inferior vena cava,superior vena cava, femoral, internal jugular, and other veins ofsimilar size and position.

Methods of Use Employing Thermoregulatory Drugs

[0374] The above description discloses mechanical methods of rewarming apatient, or portions of a patient, to minimize the deleteriousconsequences of total body hypothermia. Another procedure which may beperformed, either contemporaneous with or in place of mechanicalwarming, is the administration of anti-vasoconstriction andanti-shivering drugs. Such drugs minimize the effect of vasoconstrictionwhich may otherwise hinder heat transfer and thus cooling of thepatient. In general, hypothermia tends to trigger aggressivethermoregulatory defenses in the human body. Such drugs also prohibitresponses such as shivering which may cause damage tocardiac-compromised patients by increasing their metabolic rate todangerous levels.

[0375] To limit the effectiveness of thermoregulatory defenses duringtherapeutic hypothermia, drugs that induce thermoregulatory tolerancemay be employed. A variety of these drugs have been discovered. Forexample, clonidine, meperidine, a combination of clonidine andmeperidine, propofol, magnesium, dexmedetomidine, and other such drugsmay be employed.

[0376] It is known that certain drugs inhibit thermoregulation roughlyin proportion to their anesthetic properties. Thus, volatile anesthetics(isoflurane, desflurane, etc.), propofol, etc. are more effective atinhibiting thermoregulation than opioids which are in turn moreeffective than midazolam and the central alpha agonists. It is believedthat the combination drug of clonidine and meperidine synergisticallyreduces vasoconstriction and shivering thresholds, synergisticallyreduces the gain and maximum intensity of vasoconstriction andshivering, and produces sufficient inhibition of thermoregulatoryactivity to permit central catheter-based cooling to 32° C. withoutexcessive hypotension, autonomic nervous system activation, or sedationand respiratory compromise.

[0377] These drugs may be particularly important given the rapid onsetof thermoregulatory defenses. For example, vasoconstriction may set inat temperatures of only ½ degree below normal body temperature.Shivering sets in only a fraction of a degree below vasoconstriction.

[0378] The temperature to which the blood is lowered may be such thatthermoregulatory responses are not triggered. For example,thermoregulatory responses may be triggered at a temperature of 1-1½degrees below normal temperature. Thus, if normal body temperature is37° C., thermoregulatory responses may set in at 35° C. Thermoregulatorydrugs may be used to lower the temperature of the thermoregulatorytrigger threshold to 33° C. Use of the heating blankets described abovemay allow even further cooling of the patient. For example, to lower thepatient's temperature from 33° C. to 31° C., a 2° C. temperaturedifference, a 2 times 5° C. or 10° C. rise is surface temperature may beemployed on the skin of the patient to allow the patient to not “feel”the extra 2° C. cooling.

[0379] A method which combines the thermoregulatory drug methodology andthe heating blanket methodology is described with respect to FIG. 43.This figure is purely exemplary. Patients' normal body temperaturesvary, as do their thermoregulatory thresholds.

[0380] As shown in FIG. 43, the patient may start with a normal bodytemperature of 37° C. and a typical thermoregulatory threshold of 35° C.(step 432). In other words, at 35° C., the patient would begin to shiverand vasoconstrict. A thermoregulatory drug may be delivered (step 434)to suppress the thermoregulatory response, changing the thresholdtemperature to, e.g., 35° C. This new value is shown in step 436. Theheat transfer element may then be placed in a high flow vein, such asthe superior or inferior vena cavae or both (step 438). Cooling mayoccur to lower the temperature of the blood (step 440). The cooling maybe in a fashion described in more detail above. The cooling results inthe patient undergoing hypothermia and achieving a hypothermictemperature of, e.g., 33° C. (step 442). More cooling may be performedat this stage, but as the thermoregulatory threshold has only beensuppressed to 33° C. (step 442), shivering and vasoconstriction woulddeleteriously result. This may complete the procedure. Alternatively, anadditional drug therapy may be delivered to further lower thethermoregulatory threshold.

[0381] An alternate way to lower the thermoregulatory threshold is touse a heating blanket. As noted above, a common rule-of-thumb is that apatient's comfort will stay constant, even if their body temperature islowered 1° C., so long as a heating blanket, 5° C. warmer than theirskin, is applied to a substantial portion of the surface area of thepatient (step 444). For a 2° C.-body temperature reduction, a 10° C.(warmer than the skin temperature) blanket would be applied. Of course,it is also known that blankets warmer than about 42° C. can damagepatient's skins, this then being an upper limit to the blankettemperature. The patient's body temperature may then continue to belowered by use of a heating blanket. For each 1° C. reduction in bodytemperature (step 446), the heating blanket temperature may be raised 5°C. (step 448). After each reduction in body temperature, the physicianmay decide whether or not to continue the cooling process (step 450).After cooling, other procedures may be performed if desired (step 452)and the patient may then be rewarmed (step 454).

[0382] It is important to note that the two alternate methods ofthermoregulatory response reduction may be performed independently. Inother words, either thermoregulatory drugs or heating blankets may beperformed without the use of the other. The flowchart given in FIG. 43may be used by omitting either step 434 or steps 444 and 448.

Vasoconstrictive Therapies

[0383] High blood flow organs have a more rpaid response to hypothermiathan that of the peripheral circulation. This response may be maintainedor enhanced by applying, as an alternative method of performinghypothermia, a cooling blanket rather than a heating blanket. Thecooling blanket may serve to vasoconstrict the vessels in the peripheralcirculation, further directing blood flow towards the heart and brain.

[0384] An alternate method of performing the same function is to provideseparate vasoconstrictive drugs which affect the posterior hypothalamusin such a way as to vasoconstrict the peripheral circulation whileallowing heart and brain circulation to proceed unimpeded. Such drugsare known and include alpha receptor type drugs. These drugs, as well asthe cooling blankets described above, may also enhance counter-currentexchange, again forcing cooling towards the heart and brain. Generally,any drug or cooling blanket that provides sufficient cooling to initiatea large scale cutaneous peripheral vasoconstrictive response would becapable of forcing the cooling blood flow towards the brain and heart(i.e., the “central” volumes). In this application, the term “peripheralcirculation” or “peripheral vasculature” refers to that portion of thevasculature serving the legs, arms, muscles, and skin.

Antishiver Drugs and Regimens

[0385] Other thermoregulatory drugs are now described. Meperidine is ananalgesic of the phenyl piperdine class that is known to bind to theopiate receptor. Meperidine is also used to treat shivering due topost-operative anesthesia and hypothermia. Meperidine can also treatrigors associated with the administration of amphotericin B.

[0386] Meperidine can also be used to control shivering when hypothermiais induced clinically. During periods of ischemia, such as occurs duringa stroke or heart attack, hypothermia can protect the tissue fromdamage. It is important to be able to cool patients with out inducing ageneral anesthetic condition requiring intubation. To cool consciouspatients requires very high doses of meperidine. Cooling of patients canbe accomplished by the above noted methods such as cooling blankets (airor water) or alcohol bathing. Cooling can also be accomplished by bodycavity lavage (bladder, stomach, colon, peritoneal). The most efficientway to cool patients, as noted above for therapeutic purposes, is usingan intravascular catheter. An intravascular cooling catheter has a heatexchange region that is responsible for exchanging heat with the blood.Absorption of heat from the blood by the heat exchange region results incooling of the body. Causing mixing, or turbulence, on, or near, theheat exchange region, enhances heat transfer by intravascular methods.The heat exchanger of the intravascular catheter can have features thatinduce turbulence or mixing.

[0387] Shivering is regulated by the hypothalamus of the brain. Thehypothalamus regulates body temperature in general by controlling heatproduction and heat loss. Heat production above the base metabolic levelis produced through shivering, while heat loss is prevented byvasoconstriction, which decreases blood flow to the skin/periphery. Thenormothermic set point of the hypothalamus is approximately 37° C. Whenthe body is cooled a threshold is reached at which vasoconstriction andshivering occur. Vasoconstriction occurs approximately 0.5-1.0° C. belowthe set point, with shivering occurring 1.0-1.5° C. below the set point.The intensity of shivering increases proportionally with the differencefrom the threshold up to a maximum intensity. Meperidine lowers thethreshold at which shivering occurs, but it does not have much effect onthe gain and maximum intensity. The reduction of the shivering thresholdis proportional to the serum concentration of meperidine, such thatgreater serum concentrations cause a greater reduction in the threshold.Meperidine is believed to possess special antishivering effects, inparticular because it decreases the shivering threshold twice as much asthe vasoconstriction threshold. In addition, it prevents or managesshivering better than equianalgesic doses of other opioids.

[0388] Meperidine's antishivering effects (lowering of the shiveringthreshold) may not be related to binding of the opiate receptor.Meperidine is known to have numerous non-opioid effects such asanticholinergic action and local anesthetic properties. Further, theantishivering effects produced by meperidine are not antagonized bynalaxone, an opiate receptor antagonist. In addition, other opiates suchas morphine, pentazocine, and nalbuphine have lesser or no antishiveringactivity.

[0389] Meperidine usage has a number of undesirable side effects, andmany are related to the affinity for the opiate receptor. The mostserious is respiratory sedation, which can result in death, and may berelated to affinity for the delta opiate receptor. It has been shownthat blocking the delta opiate receptor with an antagonist can reduce oreliminate opioid induced respiratory sedation. In addition, meperidineis metabolized in the liver by n-demethylation, which produces themetabolite nor-meperidine. Nor-meperidine is known to have centralnervous system toxicity and can cause seizures. Meperidine cannot beused in patients with renal insufficiency or kidney failure due to arapid build up of the normeperidine metabolite. In addition, meperidinecannot be used in patients taking monoamine oxidase inhibitors, due tocomplications such as convulsions and hyperpyrexia.

[0390] Prodines (alpha and beta) are structurally very similar tomeperidine. They too bind to the opiate receptor, though with greateraffinity. Unlike meperidine, prodines have chirality. Chiral moleculeshave at least one asymmetric atomic center that causes the mirror imageof the base molecule to be non-superimposable on base molecule. Eachspecies, the base molecule and the mirror image, is referred to as anenantiomer.

[0391] Chiral molecules are optically active meaning each enatiomer canrotate a plane of polarized light equal but opposite directions,clockwise and counter clockwise, plus and minus. Thus if one enantiomerrotates a plane of polarized light +10 degrees {(+) enantiomer}, theopposite enantiomer will rotate light −10 degrees {(−) enantiomer)}. Forexample, the two prodines, known as alpha and beta, differ in theposition of the 3-methyl group. A chiral atomic center exists at thecarbon to which the 3-methyl group is bound and results in the variousenantiomeric species. The chemical reactions that produce chiralmolecules often produce racemic mixtures, or mixtures that containfractions of each enantiomer. A racemic mixture that contains equalproportions of each enatiomer is optically inactive.

[0392] Binding to the opiate receptor is known to be stereoselective.This means that one enantiomer has much greater affinity for thereceptor than the other enantiomer. For example, the (−) isomer ofmorphine has much greater affinity for the opiate receptor than the (+)isomer. In the case of alpha and beta prodine, the (+) isomer has muchgreater affinity for the receptor than the (−) isomer.

[0393] It is reasonable to assume that the prodines have anti-shivereffects similar to meperidine due to their structural similarity. Thisis a reasonable assumption because fentanyl, an opioid analgesic that isalso structurally related to meperidine, also has anti-shiver effects.Fentanyl, also has opiate related side effects such as respiratorysedation.

[0394] The ideal antishiver medication or regimen would have potentantishiver efficacy with little respiratory sedation or other sideeffects. One way to accomplish is to use meperidine, fentanyl, or otheropioids with antishiver effects, in combination with a delta opiatereceptor antagonist. Naltrindole or naltriben are competitiveantagonists at the delta receptor and can block the respiratory sedationcaused by fentanyl. Thus, inducing hypothermia in a conscious patientusing an intravascular cooling catheter would be accomplished using adrug regimen that included an opiate such as fentanyl or meperidine incombination with a delta receptor antagonist, such as naltrindole.

[0395] A molecule structurally similar to meperidine, but unable to bindto the opiate receptor or having antagonism at the opiate receptor,would likely possess anti-shiver effects, but not opiate relatedrespiratory sedation, since anti-shivering effects may be mediatedthrough a different receptor. This ideal anti-shiver molecule exists inthe form of the (−) isomer of alpha or beta prodine. The ratio of opiateefficacy (+/−) between the enantiomeric forms of alpha and beta prodineis at least 10 to 30 fold. Because of the structural similarity tomeperidine they would likely retain the antishiver efficacy. In ananalogous example, dextromethorphan is a morphine-based chemical that isa cough suppressant (antitussive). Dextromethorphan, which is the (+)methoxy enantiomer of (−) levorphanol, has retained the antitussiveeffects of morphine derivatives (i.e. (−) levorphanol), but lost otheropiate effects such as analgesia, respiratory sedation, and addiction.

[0396] In addition, the opiate receptor affinity of the (+) isomer ofalpha and beta prodine could also be interrupted. This can beaccomplished by adding a hydroxyl (particularly in the m position) tophenyl ring. This is particularly true of the potent opiate analgesicalpha-allylprodine, in which the 3-methyl is replaced with an allylgroup. Further, the opiate activity of (+) betaprodine isomer can besignificantly diminished by the substitution of the 3-methyl group withan n-propyl or allyl group. These modifications to the (+) isomers ofthe prodine molecules that inhibit opiate activity will not likelyeffect antishiver activity due to the structural similarity tomeperidine.

[0397] Cis-Picenadol, 1,3 dimethyl-4-propyl-4-hydroxyphenyl piperdine(cis 3-methyl, 4-propyl) is phenyl piperdine compound in which the (−)enantiomer has antagonist properties at the opiate receptor. Due to thestructural similarity to meperidine, this (−) enantiomer may haveanti-shiver activity with little respiratory sedation. It is known thatthe racemic mixture of this opioid has a ceiling effect with respect torespiratory sedation when used in animals. This ceiling effect may makeracemic picenadol a better anti-shiver drug than meperidine. Finally,tramadol may have an enantiomer that has reduced opiate activity thatcould lower the shiver threshold.

[0398] Alpha prodine has been used as an analgesic in clinical medicine,marketed under the trade name Nisentil. The drug is supplied as aracemic mixture. It is possible to separate the racemic mixture into twopure isomers and use the (−) isomer as an antishiver medication. Such aseparation can be accomplished using high-performance liquidchromatography (HPLC) using a chiral stationary phase. One such chiralstationary phase is cellulose-based and is supplied as Chiralcel OD andChiralcel OJ.

[0399] A representative example of the use of the novel antishiver, orthreshold lowering, drugs or regimen, is a clinical procedure to inducehypothermia in a patient. The patient would first be diagnosed with anischemic injury, such as a stroke or heart attack. An intravascularcooling catheter or a cooling blanket would be applied to the patient.The patient would be given an intravenous injection of the novel antishiver drug, such as (−) alpha prodine. Alternatively the patient couldbe given meperidine or fentanyl in combination with a delta opiatereceptor antagonist. Buspirone could be given in combination with eitherof the above regimens because it is know to enhance the antishivereffects of meperidine. The patient would be cooled to 32-35° C. orlower. During the maintenance of cooling which could last 12-48 hours orlonger, doses of the antishiver drug or regimen would begin to maintaina certain plasma concentration. An infusion of the novel antishiver drugcould be used to maintain the plasma concentration. When the cooling wascomplete the patient would be rewarmed and the drugs discontinued.

[0400] Another ideal antishiver drug may be nefopam. Nefopam is widelyused as an analgesic, particularly outside the U.S. While it is not ananalog of meperidine, it has similar structural and conformationalproperties. For example it has a phenyl group attached to a N-methylring, and the phenyl group prefers the equatorial position. Similar tomeperidine, nefopam is known to prevent post-operative shivering and toprevent shivering related to Amphotericin B administration. However,nefopam has less respiratory depression side effects, and is notmetabolized into a neurotoxic compound. Injectable nefopam is a racemicmixture. Analgesic activity resides in the (+) enantiomer. The (−)enantiomer may be a selective anti-shiver drug and superior to theracemic form. Combining nefopam with intravascular catheter basedcooling induction may allow for successful implementation of therapeutichypothermia.

[0401] It may also be desirable to use combinations of the compoundslisted above or combine them with other drugs that can reduce shiveringand lower the threshold. This may lower the doses needed for either drugand reduce side effects. For example, one could combine nefopam with (−)alpha-prodine, meperidine, thorazine, buspirone, clonidine, tramadol, orother medications to achieve the desired effect. The same combinationscould be used with (−) alpha-prodine. There are many other combinationsthat could be tried including combining three agents together. Thesecombinations can be used with endovascular or surface hypothermiainduction for therapeutic purposes.

[0402] While the particular invention as herein shown and disclosed indetail is fully capable of obtaining the objects and providing theadvantages hereinbefore stated, it is to be understood that thisdisclosure is merely illustrative of the presently preferred embodimentsof the invention and that no limitations are intended other than asdescribed in the appended claims. TABLE I PatientTarget-T_(Blood Sampled) 14 fr Sampling Interval Duty Cycle   4° C. 30minutes 95%   3° C. 20 minutes 93%   2° C. 15 minutes 90%   1° C.  7minutes 82%  0.5° C.  3 minutes 66% 0.25° C. 1.5 minutes  50%

[0403] TABLE II Time (seconds) Temp. ° C. from Steady State 0 ˜18.2° C.19.2° C.  10 35.5 1.9° C. 20 36.7 0.7° C. 24 36.9 0.5° C. 26 37.0 0.4°C. 29 37.1 0.3° C. 35 37.2 0.2° C. 50 37.3 0.1° C. 90 37.4 0.0

[0404] TABLE III Max Cooling Rate Max. Rewarm Catheter Size ObservedRate Observed 14 fr <8° C./Hr <4.0° C./Hr  9 fr <4° C./Hr <4.0° C./Hr

[0405] TABLE IV Current Temp. − Target Temp. 9 fr. 14 fr. 37° − 33° C. =4° C. “cooling” 60 30 minutes minutes 36° − 33° C. = 3° C. 45   22.5minutes minutes 35° − 33° C. = 2° C. 30 15 minutes minutes 34° − 33° C.= 1° C. 15   7.5 minutes minutes 34.5° − 33° C. = 0.5° C.   7.5   3.7minutes minutes 33° − 37° C. = 4° C. “warming” 60 60 minutes minutes 34°− 37° C. = 3° C. 45 45 minutes minutes 35° − 37° C. = 2° C. 30 30minutes minutes 36° − 37° C. = 1° C. 15 15 minutes minutes 36.5° − 37°C. = 0.5° C.   7.5   7.5 minutes minutes

[0406] TABLE V Interval E(O Time Run 9 fr. 14 fr. −4° C. to −3° C. 30 30−3° C. to −2° C. 20 20 warming mode {open oversize brace} −2° C. to −1°C. 10 10 −1° C. to −0.5° C.  5  5 <0.5° C.  2  1 minutes minutes 1 to 5 3 minutes  0.5° C. minutes 1 to 10  5 minutes   2° C. minutes coolingmode {open oversize brace} 2 to 20 10 minutes   3° C. minutes 3 to 30 20minutes   4° C. minutes   >4° C. 45 30 minutes minutes <−0.5 2 warmingmode {open oversize brace} minutes

[0407] TABLE VI Example Servo Error Example Pump/Power % >0.18° C. 100% 0.18° C. to 0.135° C. 75% 0.09° C. to 0.045° C. 50% 0.045° C. to 0.000°C. 25% 0.000° C.  0%

[0408] TABLE VII A1/A2 Ratio B 0.565  6 seconds 0.513  8 seconds 0.47810 seconds 0.455 12 seconds 0.439 14 seconds 0.426 16 seconds 0.415 18seconds

[0409] TABLE VIII Error Source Error Magnitude 2 S.D. Steady state errorin 0.06 C maintenance(due to system power & gain capability) Temperaturesensor accuracy <0.10 C  Hardware/signal processing 0.10 C Estimationalgorithm 0.20 C Patient rewarming during 0.05 C sampling period

1. A catheter system to change the temperature of blood by heat transfer to or from a circulating working fluid, comprising: a supply lumen to introduce a circulating working fluid to a heat transfer element; and and a return lumen to extract a circulating working fluid from the heat transfer element, the return lumen having a cross-sectional area greater than the cross-sectional area of the supply lumen to enhance flexibility of the heat transfer element.
 2. The system of claim 1, wherein the heat transfer element is made of a flexible conductive metal.
 3. The system of claim 1, wherein the heat transfer element is a balloon having a substantially straight inlet lumen and a helical outlet lumen, the helical outlet lumen helically encircling the substantially straight inlet lumen.
 4. The system of claim 3, wherein multiple helical outlet lumens are provided.
 5. The system of claim 4, wherein three helical outlet lumens are provided.
 6. The system of claim 3, wherein the inlet lumen and the outlet lumen are made of a flexible material.
 7. The system of claim 6, wherein the flexible material is rubber.
 8. The system of claim 6, wherein the flexible material is a material capable of undergoing inflation.
 9. The system of claim 1, wherein the working fluid is saline.
 10. The system of claim 3, wherein a length of the inlet lumen is between about 5 and 30 centimeters.
 11. The system of claim 3, wherein a diameter of the helical shape of the outlet lumen is less than about 8 millimeters when inflated.
 12. The system of claim 1, further comprising a working fluid supply including a pump, and wherein the pump circulates the working fluid.
 13. The system of claim 12, wherein the working fluid supply is configured to produce a pressurized working fluid at a temperature of between about −3° C. and 36° C. and at a pressure below about 5 atmospheres of pressure.
 14. The system of claim 3, wherein the outlet lumen includes a surface coating or treatment to inhibit clot formation.
 15. The system of claim 14, wherein the surface coating or treatment includes heparin.
 16. A method of providing flexibility in a catheter for use in a system to change the temperature of blood by heat transfer to or from a circulating working fluid, comprising: providing a catheter including: a supply lumen to introduce a circulating working fluid to a heat transfer element; and and a return lumen to extract a circulating working fluid from the heat transfer element, the return lumen having a cross-sectional area greater than the cross-sectional area of the supply lumen to enhance flexibility of the heat transfer element; and circulating fluid through the supply lumen and return lumen to change the temperature of the heat transfer element to a temperature different from a patient temperature, to heat or cool the patient.
 17. The system of claim 16, wherein the heat transfer element is made of a flexible conductive metal.
 18. The system of claim 16, wherein the heat transfer element is a balloon having a substantially straight inlet lumen and a helical outlet lumen, the helical outlet lumen helically encircling the substantially straight inlet lumen.
 19. The system of claim 18, wherein multiple helical outlet lumens are provided.
 20. The system of claim 19, wherein three helical outlet lumens are provided.
 21. The system of claim 18, wherein the inlet lumen and the outlet lumen are made of a flexible material.
 22. The system of claim 21, wherein the flexible material is rubber.
 23. The system of claim 21, wherein the flexible material is a material capable of undergoing inflation.
 24. The system of claim 16, wherein the working fluid is saline.
 25. The system of claim 18, wherein a length of the inlet lumen is between about 5 and 30 centimeters.
 26. The system of claim 18, wherein a diameter of the helical shape of the outlet lumen is less than about 8 millimeters when inflated.
 27. The system of claim 16, further comprising a working fluid supply including a pump, and wherein the pump circulates the working fluid.
 28. The system of claim 27, wherein the working fluid supply is configured to produce a pressurized working fluid at a temperature of between about −3° C. and 36° C. and at a pressure below about 5 atmospheres of pressure.
 29. The system of claim 18, wherein the outlet lumen includes a surface coating or treatment to inhibit clot formation.
 30. The system of claim 29, wherein the surface coating or treatment includes heparin.
 31. A method of determining pressure in a catheter for use in a system to change the temperature of blood by heat transfer to or from a circulating working fluid, comprising: providing a catheter including: a supply lumen to introduce a circulating working fluid to a heat transfer element; and and a return lumen to extract a circulating working fluid from the heat transfer element; circulating fluid via a pump through the supply lumen and return lumen to change the temperature of the heat transfer element to a temperature different from a patient temperature, to heat or cool the patient; monitoring the pump speed and current drawn by the pump and using the same in a calculation of pressure.
 32. The method of claim 31, further comprising measuring the efficiency of the pump and using the same in a calculation of pressure. 